Aminospirothiazines and processes therefor

ABSTRACT

2-AMINO-1,3-THIAZINES SPIRO FUSED TO AN OXYGENATED HETEROCYCLIC RING USEFUL AS ANTI-INFLAMMATORY, ANTIALGAL, AMOEBICDAL AND ANORETIC AGENTS AND PROCESS THEREFOR.

United States Patent 3,763,155 AMINOSPIROTHIAZINES AND PROCESSESTHEREFOR Noa] Cohen, Montclair, and Gabriel Saucy, Essex Fells,

N.Y., assignors to Hotfmann-La Roche Inc., Nntley,

NJ. No Drawing. Filed Aug. 24, 1971, Ser. No. 174,543 Int. Cl. C07d93/06 US. Cl. 260-443 R 10 Claims ABSTRACT OF THE DISCLOSURE2-aminol,3-thiazines spiro fused to an oxygenated heterocyclic ringuseful as anti-inflammatory, antialgal, amoebicidal and anoretic agentsand processes therefor.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates tointermediates for the preparation of novel spirothiazine compounds ofthe formula TN-Rz wherein R taken independently is hydrogen, loweralkyl,

lower alkenyl, aryl lower alkyl, lower alkanoyl or benzoyl; R takenindependently is hydrogen, lower alkyl,

lower alkenyl, aryl, aryl lower alkyl, or a group of the formula of oneof the formulas E -CH \Y; \Y or Y where Y is a lower alkylene group offrom one to three carbons or an ortho arylene residue; R is hydrogen,lower alkyl, phenyl, 3,5 di(lower alkyl) isoxazol 4 yl ethyl, 4,4-loweralkylenedioxyor arylenedioxy-l-pentyl or 3-cyanopropyl; n is an integerof from 1 to 3; and the tautomers, enantiomers and acid addition saltsthereof.

The compounds of Formula I may exist in various tautomeric forms when Ror R is hydrogen, depending upon the nature of R and R whether thecompound is in the crystalline state or in solution, the nature of thesolvent, the temperature, and so forth. A number of the possibletautomeric forms of compounds illustrated where R is hydrogen and R isare shown below, but for clarity of treatment and to avoid confusion,all compounds of Formula I will be depicted hereinafter in tautomericform i (i.e., endocyclic double bond .and, where appropriate,non-enolized amide) and 3,763,155 Patented Oct. 2, 1973 ice As usedthroughout the specification and the appended claims, the term alkylgroup shall mean a straight or branched chain hydrocarbon groupcontaining no unsaturation and having up to 20 carbon atoms such asmethyl, ethyl, hexyl, isopropyl, tert.-butyl, decyl, etc.; the termcycloalkyl group shall mean a saturated hydrocarbon group possessing atleast one carbocyclic ring, said ring containing from 3 to 8 carbonatoms. Examples of cycloalkyl groups are cyclopropyl, cyclopentyl,cyclohexyl, cyclooctyl, l-adamantyl and so forth. The term alkenyl groupshall mean a straight or branched chain hydrocarbon group havingolefinic unsaturation and having up to 20 carbon atoms such as vinyl,isopropenyl, 2-butenyl, 2-hexenyl, etc. The term aryl group shall mean amonocyclic or bicyclic hydrocarbon group containing aromaticunsaturation having a free valence bond from an aromatic ring. Examplesof aryl groups are phenyl, 2-naphthyl, ptolyl, p-fluorophenyl,m-methoxyphenyl, etc. The term alkoxy group includes groups up to 20atoms formed by removing the hydrogen from the hydroxyl group of astraight or branched chain alkanol. Examples of alkoxy groups includemethoxy, ethoxy, propoxy, butoxy and so forth. The term alkanoylcomprehends the residue formed by removing the hydroxyl portion from thecarboxyl moiety of an alkanoic acid having up to 20 carbon atoms.Examples of alkanoyl groups are formyl, acetyl, propionyl, pivaloyl,hexanoyl, and so forth. The term alkylene group" comprehends a straightchain hydrocarbon group containing no unsaturation and having up to 20carbon atoms with one free valence bond at each terminal carbon atom;the term ortho arylene group comprehends a group containing an aromaticring which has two free valence bonds from adjacent carbons of thearomatic ring. The term lower as applied to any of the foregoing groupsdenotes a group having a carbon skeleton containing up to and including8 carbon atoms. Examples of aryl lower alkyl groups are benzyl,2-phenylethyl, l-phenylethyl, p-methylbenzyl, p-nitrobenzyl and soforth. The term substituted as applied to a phenyl group means phenylsubstituted with one or more of the following radicals: lower alkyl,trifluoromethyl, phenyl, halogen (i.e., fluorine, chlorine, bromine, oriodine), nitro, cyano, lower alkoxy, hydroxy, amino, lower alkylamino ordi(lower alkyl)amino. The term heteroaryl group comprehends monocyclicor bicyclic groups having an aromatic ring containing at least one ringhetero atom. Examples of heteroaryl groups are furyl, thienyl, pyridyl,indolyl, pyrrolyl, pyrazinyl, pyrimidinyl, quinolyl, isoxazolyl, and soforth. The term substituted cycloalkyl group means cycloalkylsubstituted with one or more lower alkyl or phenyl groups.

Preferred compounds of Formula I are those wherein R is hydrogen and Ris a group of the formula I -R; where R; is phenyl, substituted phenylor styryl, or those where R and R taken together are phthaloyl; n is 2and R is hydrogen. Especially preferred are compounds where R is phenylmono-substituted in the meta or para position.

The compounds of Formula I can, in most instances, be prepared from thecorresponding amine of Formula II TNH,

where R, is lower alkyl, phenyl, substituted phenyl, cycloalkyl,substituted cycloalkyl, naphthyl, heteroaryl, aryl lower alkyl, styrylor the group (CH R where R is lower alkoxy or lower alkoxycarbonyl, andR m and n are as above,

can be prepared by reacting the amine of Formula II with an acylatingagent in the presence of a base. Suitable acylating agents are, forexample, acyl halides, e.g., acetyl chloride, benzoyl chloride,p-fluorobenzoyl chloride, etc.; acyl anhydrides, e.g. acetic anhydride,propionic anhydride, etc.; acyl imidazoles; acyl esters, e.g.,tosylates, mesylates, p-nitrobenzoates, etc. Preferred acylating agentsare acyl halides and acyl imidazoles. Suitable bases include alkalimetal hydroxides, e.g. sodium hydroxide; and organic amines, e.g.pyridine, triethylamine, etc. Preferred bases are organic amines,especially pyridine. No additional amine is necessary when an acylimidazole is employed as the acylating agent. The reaction may beconducted in any suitable inert organic solvent such as hydrocarbons,e.g. benzene toluene, hexane, etc.; ethers e.g. diethyl ether,tetrahydrofuran, etc.; or an excess of the amine employed in thereaction. The acylation reaction may be conducted over a broadtemperature range from about 20 to the boiling point of the reactionmedium. It is generally preferred to conduct the acylation reactionbetween 20 and 50, most preferably at about room temperature. Compoundsof Formula lb alli where R R and n are as above,

may be prepared from compounds of Formula II by reaction with a loweralkyl isocyanate, e.g., methylisocyanate; or phenylisocyanate, in aninert organic solvent. Suitable solvents include hydrocarbons, e.g.benzene, toluene, hexane, etc.; chlorinated hydrocarbons, e.g.,

. 4 1 methylene chloride, chloroform, etc.; ethers, e.g. diethylether,tetrahydrofuran, dioxane, etc.; esters, e.g. ethyl acetate; amides, e.g.dimethylformamide; and so forth. The temperature is not critical and mayrange from 0 to about C. A preferred temperature range is from about 20to about 50 C., with a temperature of about room temperatures beingespecially preferred.

Compounds of Formula Ia may be alkylated or acylated by reaction with analkylating agent or acylating agent, respectively, in the presence of astrong base. Examples of alkylating agents suitable for the presentreaction are lower alkyl, lower alkenyl or aryl lower alkyl halides,e.g., methyl iodide, ethyl iodide, benzyl chloride, etc.; lower alkyl,lower alkenyl or aryl lower alkyl sulfonyl esters, such as tosylates ormesylates. Suitable acylating agents are the same as those describedabove for the introduction of the 0 ti-RJ group. Strong bases that aresuitable for the present reaction include alkali metal hydrides, e.g.sodium hydride; alkali metal amides, e.g. sodium amide; alkali metalalkoxides, e.g. sodium methoxide; and so forth.

Suitable solvents which may be employed in the reaction includehydrocarbons, e.g. benzene, toluene, etc.; ethers, e.g. tetrahydrofuran,dioxane, etc.; amides, e.g. dimethylformamide, dimethylacetamide, etc.;sufoxides, e.g. dimethyl sulfoxide, etc.; and so forth. The reaction maybe carried out at a temperature between about 20 and 100 C. A preferredtemperature range is from about 0 to about 50 C. Room temperature isespecially preferred.

By reaction in the above-described manner, there are formed compounds ofFormula Ic Ra (Ic) where R, is lower alkyl, lower alkenyl, aryl loweralkyl,

lower alkanoyl or benzoyl and R R and n are as above.

Rs- (Id) where R is lower alkyl, lower alkenyl, aryl or aryl lower alkyland R and n are as above,

such compounds may be prepared either by removing the acyl group fromthe nitrogen atom of the appropriate compound of Formula 10 or, where Ris aryl, according to the procedure described below for the preparationof compounds of Formula Ie.

For the deacylation, it is preferred to utilize a compound of Formula Ichaving an easily removal acyl group on the nitrogen such as, forexample, formyl or acetyl. Removal of the acyl group can be effected,for example, by treatment with aqueous acid or aqueous base. Suitableacids include mineral acids, e.g. hydrochloric acid, sulfuric acid,etc.; organic sulfonic acids, e.g. p-toluenesulfuric acid; and so forth.Suitable bases include'alkali metal hydroxides, e.g. sodium hydroxide orpotassium hydroxide. The reaction may be conducted in the aqueous acidicor basic medium, with or without a co-solvent.

Suitable co-solvents include alcohols, e.g. methanol or ethanol;miscible organic ethers, e.g. tetrahydrofuran, di-. oxane; and so forth.The reaction temperature may range from about room temperature to theboiling point of the reaction medium. It is preferred to employ atemperature in the range of from 50 to 120 C.

In one aspect of the present invention, the compounds of Formula II maybe prepared by a novel procedure involving condensation of a hydroxyvinyl ketone of the formula where X is halogen selected from the groupconsisting of chlorine, bromine or iodine or a group of the formulawhere R, and R are each independently lower alkyl or taken together arelower alkylene of from four to six carbon atoms, and R and n are asabove, with thiourea. Suitable solvents include lower alkanoic acids,e.g. acetic acid; and aprotic organic solvents, e.g. acetonitrile,dimethylformamide, tetrahydrofuran, etc. The reaction may be carried outusing a temperature in the range of from below room temperature to theboiling point of the reaction medium; however, a reaction temperature ofabout room temperature is generally preferred. In a preferredembodiment, when X is the condensation reaction is carried out usinglower alkanoic acid as the reaction solvent. Especially preferred isacetic acid. The resulting thiazine of Formula 11 may be isolated eitheras the free base or as a suitable acid addition salt. Where R is otherthan hydrogen, the resulting product usually is isolated as a mixture ofisomers, which may be separated by crystallization, chromatography orother standard techniques, either as the free base or as the acidaddition salt; or the mixture may be converted to a mixture ofderivatives of, for example, Formula I which may then be separated.

Compounds of Formulae 111a and IIIb where n is 2 and R is hydrogen,lower alkyl, 3,5-di(lower alkyl)- isoxazol-4-yl-ethyl, 4,4-loweralkylenedioxyor arylenedioxy-l-pentyl are known in the art. Thecompounds where R, is phenyl are prepared in an analogous manner tothose where R is lower alkyl, starting with B-phenyl-evalerolactone. Thepreparation of compounds of Formulas 111a and IIIb where R is3-cyanopropyl is described in copending US. application No. 67,296, forsteroid total synthesis process utilizing a cyanoalkyl A-ring precursor,the inventors being Cohen, Rosenberger and Saucy, which application wasfiled Aug. 26, 1970. The compounds of FormulaIIIa or IIIb where n is lor 3 may be prepared in an analogous manner to those above-describedwhere Where R is hydrogen, compounds of Formula II may also be preparedaccording to the sequences shown in Reaction Scheme A. In one sequence,a vinyl ketone of the Formula VI is reduced to the vinyl diol VII usinga chemical reducing agent. Suitable chemical reducing agents includecomplex metal hydrides, e.g. lithium aluminum hydride or sodiumbis-Z-methoxyethoxy aluminum hydride. The reduction may be carried outin any inert organic solvent, such as hydrocarbons, e.g. benzene ortoluene; ethers, e.g. diethyl ether or tetrahydrofuran; and the like. Atemperature range of from about -20 to about 50 C. may be employed.

The vinyl diol VII is then oxidized to the ketone IIIb-l. Suitableoxidizing agents include, for example, manganese dioxide. The reactionmay be carried out in any inert organic solvent, for example,hydrocarbons, such as benzene or toluene. It is preferred to carry outthe reaction in the presence of an organic amine, in which case theintermediate vinyl ketone of Formula IIIa-l is trapped as its Mannichbase adddition product of Formula IIIb-1. Suitable amines are open chainor cyclic secondary organic acines such as diethylamine, pyrrolidine,piperidine and the like. The intermediate vinyl ketone of Formula IIIa-lmay also be trapped as an addition product with a hydrohalic acid, forexample, hydrogen chloride or hydrogen bromide, to afford thecorresponding haloketone of Formula IIIb-l. Halo ketones of FormulaIIIb-1 may be converted back to the vinyl ketones of Formula IIIa-1 bytreatment with a weak base. Suitable weak bases include tertiary organicamines, for example, pyridine, triethylamine and the like. Thiselimination reaction may be carried out in an inert organic solvent suchas a hydrocarbon, e.g. benzene 0r toluene, at a temperature betweenabout 0 and C. The reaction may be also carried out in the absence ofsolvent, i.e., using the amine reactant as the solvent.

Compounds of Formulas IIIa-l and IHb-l may then be converted tospirothiazines of Formula IIa as described above.

REACTION SCHEME A X X K 0 (CHM: 0 fln (CHM) R'OzC R'mo r0020 VI v vm X XK OH Z CH 0 CH H OH( 2) ,OH( 1) OH( 1) l I i VII IIIb-1 IX O (CHM 0 cmOH I I Ina-1 Ila where X and n are as above, Z is a ketalized oxo groupand R is lower alkyl.

Alternatively, halo ketones or amine ketones of Formula V maybe'ketalized to afford compounds of Formula VIII. Suitable ketalizationagents include for example lower alkanols, e.g. methanol, ethanol,butanol, and so forth; lower alkylene diols, e.g. ethylene glycol,2,3-butylene glycol, 1,2-butylene glycol, 1,2-propylene glycol, and soforth; ortho-arylenediols, e.g. catechol; lower alkyl orthoformates, forexample, trimethylorthoformate or triethylorthoformate; and so forth.The ketalization is carried out in the presence of a strong acid.Suitable strong acids include mineral acids, e.g. hydrochloric acid,sulfuric acid and the like; organic sulfonic acids, e.g. paratoluenesulfonic acid and the like; Lewis acids, e.g. boron trifluoride and thelike; and so forth. The ketalization reaction may be carried out in anyinert organic solvent. Suitable inert organic solvents includehydrocarbons, e.g. benzene or toluene; lower alkanols, e.g. methanol orethanol; ethers, e.g. diethyl ether or tetrahydrofuran; and so forth.The ketalization reaction may be conducted at a temperature of fromabout C. to about 150 C. The water of reaction may be removed either byazeotropic distillation or by reaction with a dehydrating agent, forexample, an alkyl orthoformate.

The ester group of compound VIII may next be reduced to afford acompound of Formula IX. Any suitable chemical reducing agent may beemployed although complex metal hydrides such as lithium aluminumhydride or sodium bis-Z-methoxyethoxy aluminum hydride are preferred.The reaction may be carried out in any inert organic solvent, such ashydrocarbons, e.g. benzene or toluene; ethers, e.g. diethyl ether ortetrahydrofuran; and the like. The temperature of the reduction canrange from about 20 to about 50 C.

The ketal of Formula IX is deketalized in a subsequent step to afford acompound of Formula IIIb-1 by reacting the ketal compound in an aqueousacidic medium. Suitable acids include mineral acids, e.g. hydrochloricacid or sulfuric acid; organic sulfonic acids, e.g. para-toluenesulfonic acid; alkanoic acids, e.g. acetic acid; and the like. Ifdesired, an organic solvent may be employed as a cosolvent. Particularlypreferred co-solvents are organic ketones, for example, acetone. Thedeketalization may be accomplished at a temperature of from about 0 C.to about 150 C.

The ketal of Formula IX may alternatively be converted to spirothiazineIla by a novel one-step reaction with thiourea. The reaction conditionssuitable for this conversion are identical to those described above forthe conversion of compounds of Formula 1112. or IIIb to those of FormulaII. However, an acid must be present in the reaction medium. The acidemployed may be a mineral acid, e.g. hydrochloric acid; an organicsulfonic acid, e.g. p-toluenesulfonic acid or a lower alkanol acid, e.g.acetic acid. In a preferred embodiment, an alkanoic acid is used as thereaction solvent. Acetic acid is especially preferred. The acid additionsalt formed can be decomposed by conventional methods.

Compounds of Formula Ie 0 (CH2) u where R is as above and R is loweralkyl, lower alkenyl, aryl or aryl lower alkyl and R and n are as above,

can be prepared from compounds of Formula IIIa or IIIb directly byreaction with the appropriate N,N-disubstituted thiourea, in the mannerdescribed above for the preparation of compound II.

Compounds of Formula Id may also be prepared in this manner from theappropriate N-monosubstituted' thiourea.

The compounds of Formula II where n is 2 and R is other than hydrogen orphenyl can be converted into medi-cinally useful steroids. Thus, thesecompounds can be condensed with, for example, a 2-alkyl-cyclopentan-l,3dione to afford compounds of Formula IV,

Where R is lower alkyl and R is as above.

This reaction is carried out in the presence of a strong acid,preferably a mineral acid, e.g. hydrochloric acid, or an organicsulfonic acid, e.g. p-toluenesulfonic acid. The reaction may beperformed in an inert reaction medium such as a hydrocarbon, e.g.benzene or toluene; an organic ether, e.g. tetrahydrofuran or dioxane,and so forth. The temperature can range from room temperature to about150 C. A prefered temperature range is -120 C.

Compounds of Formula IV generally are known intermediates which havebeen converted into steroids of the 19-nor and 9,8,10u (retro)series.The preparation of compounds of Formula IV where R is 3-cyanopropyl, andtheir conversion to known useful steroids is described in US. patentapplication Ser. No. 67,296 cited previously.

Optically active compounds of Formulas I and II can be prepared byoptical resolution of a racemic compound of Formula I or Formula II orby utilization of an op tically active compound of Formula III in thecondensation reaction with thiourea or a substituted thiourea, describedabove.

Optical resolution of racemic compounds of Formulas I and II may beaccomplished by conventional procedures such as fractionalcrystallization of the diasteromeric addition salts of compounds I or IIwith a chiral acid. Suitable chiral acids include strong acids such asorganic sulfonic acids, e.g. antipodes of camphorsulfonic acid,bromocamphorsulfonic acid, etc.; and carboxylic acids, e.g. antipodes oftartaric acid, malic acid, menthoxy acetic acid, etc.

Surprisingly, it has been found that, when racemic compounds of FormulasI or II having only one chiral center (i.e., only the spiro carbon atom)are treated with a strong chiral acid, a larger than theoretical yieldof one diastereomeric salt is obtained, indicating a dynamic equilibriumbetween the enantiomeric amines in the presence of the strong acid.Particularly preferred strong chiral acids are the antipodes ofcamphorsulfonic acid.

Reaction conditions and solvents for optical resolution of compounds Ior II are those conventionally used for optical resolutions and thechoice of a particular solvent, temperature and resolving agent willdepend upon the particular substrate to be resolved. Suitable solventsin clude lower alkanols, e.g. methanol or ethanol; lower akyl ketones,e.g. acetone; acetonitrile; ethyl acetate; and so forth.

Conversely, it has been found that an optically active compound ofFormula I or Formula II having only one chiral center, as describedabove, is racemized by treatment with a strong achiral acid. Suitablestrong "achiral acids include mineral acids, e.g. hydrochloric acid andsulfuric acid; organic sulfonic acids, e.g. p-toluene-sulfonic acid; andthe like. The quantity of acid that can'be em ployed is in the broadrange of from about .1 mole percent to greater than mole percentrelative'to the sub strate to be racemized. Generally about 1 toabout 20mol percent of acid is preferred.

Suitable solvents include lower alkanols, e.g. methanol or ethanol;alkyl ketones, e.g. acetone; acetonitrile; ethyl acetate;dimethylformamide or mixtures of the above with water. The reactiontemperature can vary from about to about 150 C. A preferred temperaturerange is from about 50-100" C.

The compounds of Formula II are useful as intermediates for thepreparation of medicinally valuable steroids as Well as being precursorsfor the preparation of compounds of Formula I. Furthermore, thecompounds of Formula II exhibit biological activity and are useful asanti-inflammatory agents, antialgal agents, amoebicides and anoreticagents.

The anti-inflammatory activity of compounds of Formula II may bedemonstrated in warm-blooded animals by the carrageenin antiedema ratpaw test. In this test, sixty male albino rats of the Royal Hart strain,weighing 125- 155 grams, in groups of six are given 10 ml. of vehicleper kilogram of body weight. Water is given to bring the total volume toml. in each animal. The vehicle contains the test compound for thetreatment groups. One hour later 0.05 ml. of a 1% type #7 carrageenin innormal solution is injected into the right rat hind paw. The paw volumeis measured immediately after the injection of the phlogistic agent andagain three hours later. The difference is recorded as volume of edema.Paw volume is measured by immersion of the paw into a column of Hg to anink mark exactly at the level of the lateral malleolus. The initial andfinal paw volume is measured and the average volume edema in rat paw iscalculated as the difference between the average final paw volume andaverage initial paw volume. The percent inhibition is calculated bysubtracting the average control edema from the average treatment edema,dividing by the average control edema, and multiplying by 100. Thepercent inhibition is plotted against dose and the dose required toproduce a 30% reduction in edema is estimated. This is the ED A compoundexhibiting an ED of less than 100 mg./kg. p.o. in the test is consideredto be active.

When utilized in the above test, racemic 2-amino-7-oxa-S-thia-l-azaspiro[5.5]undec-1-ene was found to be active.

The compounds of Formula I exhibit analgesic, antiinflammatory,anti-pyretic and diuretic activity. Both antipyretic and analgesicactivity may be measured, for example, by means of the yeast-inflamedfoot test. In this test, 30 male rats are divided into six groupscontaining five rats per group. Control animals are given 1 cc./100 g.body weight of the vehicle. The test drug animals are given 200 mg./ kg.of the drug in a concentration of 2% either orally or subcutaneously.Soluble and insoluble compounds are administered orally in an aqueoussuspending vehicle. One hour after administration of the drug the ratsare injected with 0.1 ml. of a 2% suspension of Brewers yeast beneaththe plantar surface of the foot. To determine anti-pyretic activity, twohours after drug injection and one hour after the irritant, thetemperatures of the inflamed foot, the normal foot and the rectum arerecorded with the help of a thermocouple. Results are reported asdegrees change from control. A compound causing a 0.2 drop in inflamedfoot temperature when administered at 10 mg./kg. p.o. is consideredactive in the test.

For the measurement of analgesic activity, the pain threshold wasmeasured as the amount of pressure in the mm.-Hg required to induce theflight reaction (struggle) when applied to the foot. Air pressure froman air line was admitted through a needle valve to a 10 ml. syringemounted with the plunger directed downward, to which was connected to ashort bullet-shape metal peg. The pressure was applied through the metaltip to the plantar surface of the rats foot at the rate of mm.-Hg persecond. The end point was reached when the rats struggle. One group offive rats acts as control. The pain threshold is the amount of pressurein mm.-Hg required to induce the flight reaction. Pain results areobtained by subtracting control pressure readings from treated pressurereadings for the inflamed foot. The results are expressed as change inpain threshold in mm.-Hg in the inflamed foot. The ED is that dose whichproduces an increase in pain threshold of 50 mm.-Hg above control valuesin the inflamed foot. A compound exhibiting an ED of less than 200mg./kg. p.o. in the test is considered to be active. When employed inthe above two tests, the following compounds were found to be active:

Racemic 2-phthalimido-7-oxa-3-thia-1-azaspiro [5.5

undecl-ene.

Racemic 2-p-fluorobenzamido-7-oxa-3-thia-1-azaspiro [5.5]undec-1-ene.

Racemic Z-cinnamamido7-oxa-3-thia- I-azaspiro [5.5

undecl-ene.

Racemic 2-p-nitrobenzamido-7-oxa-3-thia-1-azaspiro [5.5]undec-1-ene.

Racemic 2- (3 ,4-dimethoxybenzamido 7-oxa-3-thia-1- azaspiro[5.5]undec-1-ene.

Racemic 2-p-cyanobenzamido-7-oxa-3-thia-l-azaspiro [5 .5 undecl-ene.

Racemic 2-p-methylbenzamido-7-oxa-3-thia-l-azaspiro [5.5]undec-1-ene.

Racemic-Z-m-fluorobenzamido-7-oxa-3 -thial azapiro [5.5]undec-1-ene.

The above results demonstrate the utility of the compounds of Formula Ias anti-pyretic and analgesic agents.

That the above compounds are useful as therapeutic agents is furtherdemonstrated by their generally low toxicity as expressed as LD Forexample, the LD for intraperitoneal administration in mice of racemic2-pfluorobenzamido 7 oxa-3-thia-1-azaspiro[5.51undec-1- ene is greaterthan 400 mg./kg.

The compounds of Formulas I and II can be used in the form ofconventional pharmaceutical preparations. For any particular subject thespecific dosage and dosage regimen should be adjusted to individual needand the professional judgment of the person administering or supervisingthe administration of the compound. The daily dosage regimen may consistof unit or divided dosage forms. The conventional pharmaceuticalpreparations containing the compounds of Formula I or Formula II cancontain them in admixture with conventional organic or inorganic inertcarrier materials suitable for enteral or parenteral administration suchas, for example, water, gelatin, lactose, starch, talc, vegetable oil,gum, polyalkylene glycols, Vaseline and the like.

The preparations can be in conventional solid form, such as tablets,dragees, suppositories or capsules; or in conventional liquid form, suchas solutions, suspensions or emulsions. They can be subjected toconventional pharmaceutical expedients such as sterilization and maycontain conventional pharmaceutical additives such as preservatives,stabilizing agents, wetting or emulsifying agents, salts for adjustingosmotic pressure, buffers, etc. They also can contain otherpharmaceutically active ingredients.

The following examples are illustrative of the invention but notlimitative thereof. All temperatures are stated in degrees centigradeand all compounds are racemic unless otherwise specified.

Example 1 A solution of 1.628 g. (0.0059 mole) of8-(4,4-phenylenedioxy-l-pentyl)-6-valerolactone in 15 ml. of drytetrah'ydrofuran was stirred and cooled in a Dry Ice-acetone bath while5 ml. (0.01 mole) of 2 M vinylmagnesium chloride in tetrahydrofuran wasadded, dropwise, over three minutes, keeping the internal temperaturebelow -50. The resulting mixture -was stirred at -50-55 for 25 minutesthen cautiously decomposed with 5 ml. of methanol, poured into ice and20 ml. of saturated ammonium chloride and worked up with ether in theusual manner to afford 1.72 g. of 6- (4,4-phenylenedioxy-1-pentyl)-2-vinyl-tetrahydropyran 2 01 (alternative nomenclature11,1l-phenylenedioxy-dodoec-1-en 7 o1 3- one) as a yellow oil. 1

Example 2 The vinyl adduct prepared in Example 1 was treated with 0.45g. (0.0059 mole) of thiourea and ml. of glacial acetic acid. The mixturegot slightly warm and the thiourea slowly dissolved. The resultingyellow solution was stirred at room temperature for 18.5 hours thendiluted with benzene and a small amount (-70 mg.) of white solid wasfiltered. The filtrate was concentrated at reduced pressure to a viscousorange oil which was dissolved in ether and the ether solution waswashed three times with water. The combined aqueous washings wereextracted once with ether then concentrated at reduced pressure to 1.689g. of foam composed of a mixture of acetate salts. This material wasredissolved in m1. of water and basified to pH 8 with saturated aqueoussodium bicarbonate. The dense white precipitate was filtered withsuction, washed well with water and dried under high vacuum giving 1.175g. (55%) of oflwhite solid 2-amino- 8-[4,4-phenylenedioxy 1 pentyl] 7oxa 3 thia-lazaspiro[5.51undec-1-ene. Several recrystallizations fromacetonitrile gave product, M.P. 144145,

v5.1. 3440, 3300, 3250, 1650, 1590, 1480, 1240 and 740 cmf A332? 283 m(e 4170), M5? 237 m, (e 8150) 6 1.62, 4.53, 6.75, p.p.m.; mass spectrum:m/e 36 (M+), 334 (M28).

Analysis.Calcd. for C H N OgS (percent): C, 62.94; H, 7.24; N, 7.73; S,"8.84. Found (percent): C, 63.24; H, 7.32; N, 7.74; s, 8.88.

Example 3 A solution of 10 g. (0.045 mole) of 6-[3,5-dimethyl-4-isoxazolyl)ethyl] 8 valerolactone in 150 ml. of dry tetrahydrofuranwas stirred and cooled with a Dry Iceacetone bath -while 37.5 ml. (0.075mole) of 2 M vinylmagnesium chloride in tetrahydrofuran was addeddropwise at such a rate as to keep the internal temperature atapproximately -60. The resulting mixture was stirred at 70 for minutesthen decomposed with 5 ml. of methanol, poured onto a mixture of ice, 24g. of ammonium chloride and 8 ml. of glacial acetic acid and worked upwith ether in the usual manner to afiord6-[(3,5-dimethyl-4-isoxazolyl)ethyl] 2 vinyl tetrahydropyran- 2-01[alternative nomenclature 9 (3,5 dimethylisoxazol-4-y1)-non-1-en-7-ol-3-one] Example 4 The material prepared in Example 3was treated with 3.4 g. (0.045 mole) of thiourea and 50 ml. of glacialacetic acid. The resulting solution was stirred at room temperature forhours and then concentrated at reduced pressure. The residue was treatedwith ether and 1 N aqueous hydrochloric acid. The aqueous acidic layerwas separated and washed once with ether (the combined ether solutionswere discarded) and then basified with 10% aqueous sodium hydroxidesolution and worked up with ether in the usual manner giving 11.0 g. ofa mixture of isomers of 2-amino-8-[2 (3,5 dimethyl-4-isoxazolyl)ethyl]-7-oxa-3-thia 1 azaspiro[5.5]undec-1- ene.

In another experiment, the crude product, prepared in the mannerdescribed above (7.2 g.) was recrystallized four times 56m acetonitrilegiving 2.8 g. of colorless solid, M.P. 124-126 which was essentially onepure isomer. An analytical specimen was obtained by repeatedrecrystallization of a sample from acetonitrile as white solid, M.P.126-127;

75,53 8500, 8400, 1640, 1580 cm." x593? 210 215 mu 3.85, 2.28, 2.19,3.06, 2 p.p.m.; mass spectrum: m/e 309 (M''), 281 (NI-28).

. 3500, 8400, 1540, 1620, 1580, cmr 329 215 1M max. (6 12400 85335 4.89,8.5, 8.0, 2.80, 2.20 p.p.m.; mass spectrum: m/e 309 (M*'), 281 (M-28).

Analysis.-Calcd. for C H N O S' (percent): C, 58.23; H, 7.49; N, 13.58;S, 10.35. Found (percent): C, 58.44; H, 7.55; N, 13.55; 5, 10.36.

Example 5 fi-Phenyl-a-valerolactone was prepared by sodium borohydridereduction of 4-benzoylbutyric acid. The material obtained had M.P.72-74" (reported M.P. 74-76") after recrystallization frombenzene-hexane.

Example 6 A solution of 10.4 g. 0.059 mole) of B-phenyl-E-valerolactonein ml. of dry tetrahydrofuran-Was stirred and cooled with a DryIce-acetone bath While 50 ml. (0.1 mole) of 2 M vinyl magnesium chloridein tetrahydrofuran was added dropwise over 25 minutes keeping theinternal temperature between -5'0 and --60. The precipitated startinglactone slowly dissolved and the resulting solution was stirred at --60to 70 for 15 minutes. After cautious, dropwise addition of 10 ml. ofmethanol while still cold, the reaction mixture was poured onto amixture of ice and saturated ammonium chloride and worked up with ethergiving 12.65 g. of crude 6-phenyl- 2-vinyl-te't-rahydropyran 2-01(alternative nomenclature 7-phenyl-hept-1-en-7-ol-3-one) as a viscousyellow oil.

Example 7 The product from Example 6 was treated with 4.5 g. (0.059mole) of thiourea and 50 ml. of glacial acetic acid and the resultingmixture (mildly exothermic on mixing reactants) was stirred at roomtemperature for 18 hours. The resulting orange solution was concentratedat reduced pressure to a syrupy residue which was treated with ether and1 N aqueous hydrochloric acid. This caused the formation of a denseprecipitate which was suction filtered, washed well with ether and setaside. The combined filtrate and washings was separated into an etherlayer and an aqueous layer. The aqueous layer was extracted once morewith ether and set aside. The combined ether extracts were washed withbrine, dried (MgSO filtered and concentrated at reduced pressure giving4.2 g. of neutral by-products as an orange oil.

The solid and aqueous acidic solution above which had been set asidewere combined and basified with 10% aqueous sodium hydroxide. Workup inthe usual manner with methylene chloride gave 11.4 g. of an orangesemisolid mixture of isomers of 2-amino-8-pheny1-7-oxa-3-thia-l-azaspiro[5.51undec-1-ene. A 10.9 g. sample of this material wasdissolved in 25 ml. of hot acetonitrile and added to 5.3 g. of maleicacid dissolved in 25 ml. of hot acetonitrile. The resulting solution wasconcentrated at reduced pressure and the residue was trituratedunderether giving a solid. Filtration and ether washing gave tan solid, M.P.159-165 composed of a mixture of maleate salts of the above isomer-s.This material was digested in 75 ml. of boiling acetonitrile thenchilledandfiltered. After drying, one of the isomeric maleates wasobtained as an off-white solid, M.P. 169-170.

Analysis.Calcd. for C H N O S' (percent):.; .C, 57.13; H, 5.86;-N, 7.40;S, 8.47. Found (percent): C, 57.45; H, 5.98; N, 7.53; S, 8.47.

13 In another experiment the crude mixture of bases (3.1 g.) wastriturated with ethyl acetate giving 0.79 g. of white solid, M.P.164-165. Recrystallization of a sample obtained in this manner fromacetonitrile gave the analytical specimen of the other isomer as Whitesolid, M.P. 166-167.

ggf 3500, 3400, 1070, 1050, 1010 ant- A3 3 203 10200), 255 (200), 201(182) m 1, 7.3 0.0, 4.0, 2.91, 1.01, p.p.m.: mass spectrum: m/e 262 (M234 (M-28).

' Analysis.Calcd. for C H N OS (percent): C, 64.10; H, 6.92; N, 10.68;S, 12.20. Found (percent): C, 64.31; H, 6.86; N, 10.74; S, 12.07. t

The filtrate after removal of this second isomer was diluted to 100 ml.and stirred with 60 g. of grade I alumina then filtered. Concentrationof the filtrate gave 0.4 g. of the first isomer which crystallized onstanding. Recrystallization from benzene-hexane gave the analyticalspecimen as white solid, M.P. 102-103 43,59 3500, 3400, 1030, 1580 ant-455;, 3400, 3300 3250, 3125, 1640, 1600, 1580 cmf 25,22 206 m (6 10000);8%,? 8.30, 5.11, 4.50, 3.10, 2 p.p.m.; mass spectrum: m/e 262 (M*), 234(M-28).

Analysis.Calcd. for C H N OS (percent): C, 64.10; H, 6.92; N, 10.68; S,12.20. Found (percent): C, 64.27; H, 6.85; N, 10.60; S, 12.07.

Example 8 'Mannich base6-phenyl-2-(Z-diethylaminoethyl)-tetrahydropyran-Z-ol was prepared bytreatment of crude vinyl adduct (prepared as described in Example 6)with diethylamine. The crude Mannich base was purified by extractionwith acid. A yellow oil was obtained.

A'mixture of 1.55 g. (0.0056 mole) of Mannich base prepared in thismanner, 0.44 g. (0.0058 mole) of thiourea, 5 ml. of glacial acetic acidand 15 ml. of toluene was stirred and refluxed for 75 minutes. Theresulting solution was cooled, diluted with ether and treated with 60ml. of 3 N aqueous H01. The precipitated solid was filtered with suctiongiving 1.2 g., M.P. 230-231" dec. This material was basified withaqueous sodium hydroxide and worked up with methylene chloride in theusual manner giving 1.1 g. of a mixture of the two isomers prepared inExample 7. Trituration with benzene and filtration gave 0.394 g. ofsolid, M.P. 160-161 which was largely the second isomer. Concentrationof the filtrate gave 0.25 g. of solid, M.P. 102-103" which was largelythe first isomer.

Example 9 A solution of 18.9 g. (0.166 mole) ofd-methyl-fi-valerolactone (prepared from 4-acetylbutyric acid by sodiumborohydride reduction) in 100 ml. of dry tetrahydrofuran was stirred andcooled to 60 with a Dry-Ice acetone bath (the lactone precipitated)while 150 ml. (0.3 mole) of 2 M vinylmagnesium chloride was addeddropwise over 20 minutes (the lactone dissolved). The temperature waskept below 45. After stirring for 10 minutes at -60, the reactionmixture was cautiously decomposed by dropwise addition of 35 ml. ofmethanol while still cold, then poured on a mixture of ice and saturatedaqueous ammonium chloride. Workup with ether in the usual mannerafforded crude 6-methyl-2-vinyl-tetrahydropyran-Z-ol (alternativenomenclature 7-hyd1'oxy-0ct-1-en-3-one) Example 10 The vinyl adductprepared in Example 9 was treated with 12.63 g. (0.166 mole) of thioureaand 100 ml. of glacial acetic acid. The reaction was stirred at roomtemperature for 20 hours then the resulting orange solution wasconcentrated at reduced pressure. The syrupy residue was treated withether and 1 N aqueous hydrochloric acid.

14 The aqueous layer was separated and washed once with ether then setaside. The combined ether extracts were washed once with brine, dried(MgSO filtered and concentrated at reduced pressure giving 9.5 g. ofoily neutral by-products.

The aqueous acidic solution which had been set aside was made alkalinewith 10% aqueous sodium hydroxide and worked up with methylene chloridein the usual manner giving 23.7 g. of an oily mixture of isomers of 2-amino-8-methyl-7-oxa-3-thia 1 azaspiro[5.5]undec-lene. This material wastriturated with ether and refrigerated. Suction filtration gave 3.8 g.of a pale-yellow solid, M.P. 114-1155", TLC analysis indicated this waspredominantly one isomer.

Concentration of the combined ether filtrate and washings above gave18.4 g. of yellow oil which was a mixture of isomers. This was dissolvedin 100 ml. of ether and treated with a solution of 10.7 g. of maleicacid in ml. of ethyl acetate. The resulting mixture was treated with ml.of ether and crystallization was induced by scratching. Afterrefrigeration, the precipitated solid was filtered, washed with etherand dried giving 22.5 g. of yellow solid. Recrystallization from 40 ml.of acetonitrile gave 17.2 g. of slightly elf-white solid, M.P. -144(mixture of isomeric maleate salts).

Analysis.Calcd. for C19H15N2OS'C4H4O4 (percent): C, 49.36; H, 6.37; N,8.86; S, 10.12. Found (percent): C, 49.26; H, 6.28; N, 8.85; S, 10.01.

In another experiment, the crude mixture of isomers (3.6 g.) wastriturated with benzene and filtered giving 0.55 g. of solid, TLCanalysis of which indicated it was essentially the pure second isomer.Recrystallization from benzene containing a few drops of acetonitrilegave white solid, M.P. 144-145.

155,9 3500, 3400, 1050, 1025, 1580 ornf x533? 202 my. (9 19050), 531,5207 m (6 12650), 2215 227 my (6 8000); 335,9 4.07, 3.07, 2.03, 1.20p.p.rn.; mass spectrum: m/e 200 (M 172 (M-28).

Analysis.-Calcd. for C H N OS (percent): C, 53.98; H, 8.06; N, 13.99; S,15.98. Found (percent): C, 54.04; H, 8.15; N, 13.83; S, 15.74.

The combined mother liquor from the above filtration was concentratedand the residue purified by dry-column chromatography on 1 kg. of gradeIII alumina (2" x 24" column). After development with 700 ml. of 9:1ethyl acetateztriethylamine, the bands were eluted with methanol giving1.1 g. of the first isomer, 0.5 g. of the second isomer and 0.6 g. ofmixture. The oily first isomer thus obtained could not be induced tocrystallize but was treated with 0.58 g. of maleic acid and theresulting maleate salt recrystallized from ethyl acetate thenacetonitrile giving white solid M.P. 139141.

A 209 my (6 26500) Analysis.-Calcd. for C H N O S (percent): C, 49.36;H, 6.37; N, 8.86; S, 10.12. Found (percent): C, 49.47; H, 6.50; N, 8.75;S, 10.14.

The free base regenerated from this maleate was an oil.

4,9 5,9 3500, 3400, 1030, 1020 (sh), 1580 01117 xii? 204 (e 8715); 89,394.55, 4.13, 3.00, 1.10 p.p.rn.; mass spectrum: rn/e 200 (M+), 172 (M28).

Example 11 15 mixture of isomers prepared in Example 10. Triturationwith benzene and filtration gave 1.65 g. of solid which was largely thesecond isomer. The mother liquors contained mainly the first isomer.

Example 12 A mixture of 14.07 g. (0.07 mole) of2-(diethylaminoethyl)tetrahydropyran-Z-ol, 5.6 g. (0.073 mole) ofthiourea, 70 ml. of glacial acetic acid and 220 ml. of toluene wasstirred and refluxed for 75 minutes. The resulting solution was cooledand extracted with 1 N aqueous hydrochloric acid. The aqueous acidicsolution was made alkaline with 10% aqueous sodium hydroxide and workedup with ether in the usual manner giving 10.7 g. of yellow solid.Recrystallization from 60 ml. of ethyl acetate gave 7.4 g. of2-amino-7-oxa-3-thia 1 azaspiro[5.5]undec-l-ene, M.P. 138-140". Ananalytical specimen was obtained by further recrystallization from ethylacetate as white solid, M.P'. 139-140.5.

3375, 3300, 3250, 3150, 1640, 1590 cm." A

A 208 mp (e 27400).

max.

Analysis.--Calcd. for C H N OS-C H O' (percent): C, 47.68; H, 6.00; N,9.27; S, 10.59. Found (percent): C, 47.41; H, 5.78; N, 9.18; S, 10.71.

The starting material, 2-(2-diethylaminoethyl) 2-hydroxy-tetrahydropyran was prepared as follows: 25.2 g. of6-heptan-1,5-diol in 1,2-dichloroethane Was maintained under nitrogenand treated with cooling with 100 ml. of diethylamine and 208 g. ofactivated manganese dioxide. After stirring at room temperature undernirtogen for one day, the mixture was filtered and the residue washedwith benzene. The combined filtrates were evaporated to aiford the crudeproduct as a brown oil. The crude product could be purified byextraction into dilute hydrochloric acid, neutralization andreextraction into an organic solvent. An analytical sample of2-(Z-diethylaminoethyD-Z- hydroxy-tetrahydropyran was obtained bypurifying the above sample on a column of alumina (III).

Analysis.Calcd. for C H NO (percent): C, 65.63; H, 11.52; N, 6.95. Found(per-cent): C, 65.80; H, 11.52; N, 6.69.

Example 13 A solution of 0.15 g. of (-+)-2-p-fiuorobenzamido-7-oxa-3-thia-1-azaspiro[5.5]undec 1 ene( [01] '+33.27 (c.=1, CHCl preparedas described in Example 50, infra, and 0.01 g. of p-toluenesulfonic acidmonohydrate in ml. of ethanol was heated on a steam bath for minutes,then poured into saturated aqueous sodium bicarbonate solution. Themixture was extracted with methylene chloride. The methylene chlorideextracts were combined, washed with brine, dried, filtered andconcentrated at reduced pressure giving 0.142 g. of colorless solid,racemic 2-p-fluorobenzamido-7-oxa-3-thia 1 azaspiro- [5-;.5]undec 1 ene,M.P. 147-149 [01],; 0 (c. =1, CHCl Example 14 A solution of 0.56 g.(2.14 mmoles) of a crude mixture of isomeric aminothiazines prepared asin Examples 7 and 8 in 3 ml. of acetic anhydride and 6 ml. of pyridinewas allowed to stand at room temperature for 19 hours, then concentratedat reduced pressure. The residue was treated with saturated, aqueoussodium bicarbonate and extracted with ether. The ether layer wasseparated and the aqueous layer was extracted once with ether. Thecombined ether extracts were washed three times with 1 N aqueoushydrochloric acid then discarded. The compure isomer as a colorlessglass which could not be in-.

duced to crystallize. Drying a sample for several days under high vacuumaiforded an analytical specimen.

15 9 203 13930 235 (7250), 262 (11650); 151:? w 224 11500 244 (12200m,.; 73,19 3400, 1700, 1595, 1550 cmf 3252 2.14, 2.75, 3.51, 4.76, 7.30p.p.m.; mass spectrum: m/e 304 (M+).

Analysis.Calcd. for C16H20N2O2'S (percent): C,

63.12; H, 6.64; N, 9.20; S, 10.53. Found (percent): C,;

63.42; H, 6.71; N, 9.03; S, 10.57. The fractions eluted with 1:1benzenetether and ether gave 0.180 g. of pure second isomer as apale-yellow solid.

Two recrystallizations from benzene-hexane gave the analytical specimenas flufiy, white needles, M.P. 144- x532? 210 (10500), 264 (14250); A54?240 (7300) m 12.12. 226 (11500), 245 (12120 51 ,435,9 3400, 1710, 1600,1550 cm." 6 9 ,9 9 2.09, 2.77, 3.21, 4.56, 7.32 p.p.m.,' mass spectrum:m/e 304 (M'), 276 (M-28).

Analysis.Calcd. for C H N O S (percent): C, 63.12 H, 6.64; N, 9.20; 8,10.53. Found (percent): C, 63.06; H, 6.73; N, 9.22; S, 10.50.

Example 15 A 1 g. (0.05 mole) sample of a mixture of amines prepared asin Examples 10 and 11 was dissolved in 10 ml. of pyridine and 5 ml. ofacetic anhydride was added. The resulting solution was kept at roomtemperature for 3.25 hours, then concentrated at reduced pressure. Theresidue was dissolved in ether and the ether solution was washed threetimes with 1 N aqueous hydrochloric acid. The combined acid extractswere washed once with ether and the combined ether solutions discarded.The acid solution was basified with 10% aqueous sodium hydroxide,saturated with salt and worked up with ether in the usual manner giving0.889 g. of a mixture of isomers of 2- acetamido-8-methyl-7-oxa-3-thia 1azaspiro[5.5]undec- 1-ene as a yellow gum. This material was chromato-vgraphed on 45 g. of silica gel. The fractions eluted with 4:1benzenezether furnished 0.152 g. of one pure isomer. The fractionseluted with 1:1 benzenezether and ether gave 0.573 g. of the other pureisomer.

A sample of the first isomer purified in this manner was recrystallizedtwice from hexane giving the analytical specimen as white solid, M.P.113114.5.

1 220 (6250 23s (6650), 266 (13300) mm mat. max. 3400, 1700, 1595, 1550cmr 39.5,? 1.12, 2.12, 2.72, 3.53, 3.78 p.p.rn.; mass spectrum: m/e 242(M+), 227 (M-15), 214 (M-28).

Analysis.-Calcd. for C11H18N2O2S (percent): c, 54.53;

H, 7.49; N, 11.56; S, 13.21. Found (percent): C, 54.37;-

(percent) C,

Example 16 A solution of 8.05 g. (0.0433 mole) of amine prepared as inExample 12 in 64 ml. of pyridine and 40 ml. of acetic anhydride was keptat room temperature for 4.5 hours, then concentrated to dryness ataspirator pressure. The residue was dissolved in ether and the ethersolution was washed with two 25 ml. portions of 1.8 N aqueoushydrochloric acid solution. The combined aqueous acid extracts werewashed once with ether and the combined ether solutions were discarded.The acid solution was chilled, basified (pH 8-9) with 40 ml. of 10%aqueous sodium hydroxide, saturated with salt and worked up with etherin the usual manner. This aflforded 9.5 g. of pale-yellow crystalline 2acetamido 7 oxa-3-thia- 1 azaspiro[5.5]undec-1-ene. A sample from asimilar run was chromatographed on silica gel (eluted with 3:1benzene-ether to ether) and recrystallized twice from benzene-hexanegiving an analytical specimen as colorless solid, M.P. 110-111.5

max.

219 (7050), 236 (6570), 263 (13100) my; vCHCh Example 17 A solution of0.927 g. (3 mmoles) of a mixture of aminothiazines prepared as inExample 4, 0.375 g. (3.34 mmoles) of 2 methylcyclopentane 1,3 dione and0.12 g. of p-toluenesulfonic acid monohydrate in ml. of Water and ml. ofdioxane was stirred and refluxed for 92 hours. The resulting solutionwas cooled and poured into dilute aqueous hydrochloric acid and workedup in the usual manner (the ether extracts were additionally washedtwice with saturated aqueous sodium bicarbonate solutior1-the aqueousacidic solution was saved for recovery of starting material) giving 0.57g. of an orange oil. This material was stirred and refluxed in ml. ofbenzene containing 29 mg. of p-toluenesulfonic acid monohydrate for 40minutes. A Dean-Stark trap was used to remove water. The resulting greensolution was cooled, diluted with ether and Washed with aqueous sodiumbicarbonate. The usual workup gave 0.47 g. of crystalline 3 [2 (3,5dimethyl 4 isoxazolyl)ethyl]-6a 8- methyl 1,2,3,5,6,6ahexahydrocyclopenta[f][1]benzopyran-7 (8H)-one. This material waschromatographed on 25 g. of silica gel. The fractions eluted with 19:1benzeneether afforded 0.398 g. of essentially pure material.Recrystallization from 2 propanol gave 0.307 g. of yellow crystals, M.P.107ll0 (reported M.P. 113-116),

Analysis.--Calcd. for C H NO (percent): C, 73.36; H, 7.70; N, 4.28.Found (percent): C, 73.60; H, 7.45; N, 4.20.

Example 18 A solution of 29 g. (0.226 mole) of fi-ethyl-fi-valerolactonein 130 ml. of dry tetrahydrofuran was stirred with cooling to 60 (DryIce-acetone bath) while 200 m1. of 2.6 M vinylmagnesium chloride intetrahydrofuran was added dropwise over 0.5 hour, keeping thetemperature between --50 and --60. The mixture was stirred at -65 for 10minutes then treated cautiously with 30 ml. of methanol keeping thetemperature below --45. After pouring into a mixture of ice and ammoniumchloride, the organic products were extracted three times with ether.The combined organic extracts were washed once with brine, dried overanhydrous magnesium sulfate and concentrated at reduced pressure giving37.2 g. of orange 18 oily, 6 ethyl 2 vinyl-tetrahydropyran-Z-ol(alternative nomenclature 7-hydroxy-non-1-en-3-one).

This material was immediately treated with 17.2 g. (0.226 mole) ofthiourea and 140 ml. of glacial acetic acid. The resulting mixture wasstirred at room temperature for 16.5 hours then the acetic acid wasremoved at reduced pressure.

To the residue was added ml. of 3 N aqueous hydrochloric acid and 50 ml.of water and the entire mixture was extracted twice with ether. Theether ex tracts were discarded. The aqueous solution was chilled in iceand the precipitated solid was filtered and washed with ice water. Afterdrying, 12.7 g. of almost colorless 2 amino 8 ethyl7-oxa-3-thia-1-azaspiro[5.5]undeel-ene hydrochloride, M.P. 213-2145 dec.was obtained. A sample was recrystallized twice from water giving ananalytical specimen, as slightly off-white solid, M.P. 211- 212".

Analysis.-Calcd. for c,,,H,,N,os-Hc1 (percent): C, 47.89; H, 7.64; N,11.17; S, 12.78. Found (percent): C, 48.12; H, 7.75; N, 11.44; S, 12.31.

The combined acidic aqueous filtrate and washings above were madealkaline with concentrated ammonium hydroxide and extracted three timeswith methylene chloride. The combined organic extracts were dried overanhydrous magnesium sulfate, filtered and concentrated at reducedpressure giving 19.8 g. (41%) of free amine (mixture of isomers).

Example 19 A solution of 1.42 g. (6.63 mmoles) of the crude, oily freebase mixture prepared in Example 18 in 10 ml. of pyridine and 6 ml. ofacetic anhydride was kept at room temperature for four hours thenconcentrated at reduced pressure. The residue was dissolved in ether andwashed twice with 5 ml. of 1.8 N aqueous hydrochloric acid. The combinedacid washes were extracted once with ether and the ether solutionscontaining neutral impurities were discarded.

The acid solution was made alkaline with potassium carbonate andextracted with ether twice. The ether extracts were combined, dried overanhydrous magnesium sulfate, filtered and concentrated at reducedpressure giving 1.0 g. of a yellow oil composed of a mixture of isomersof Z-acetamido-8-ethyl-7-oxa-3-thia-l-azaspiro[5.5] undec-l-ene.

This material was chromatographed on 50 g. of silica gel. Fractionseluted with 4:1 benzenezether gave 0.443 g. of one isomer as apale-yellow oil which crystallized after a long period of refrigeration.

Elution with 1:1 benzenezether and ether gave 0.358 g. of the otherisomer as a pale-yellow oil which also crystallized after storage at 0.

Analytical samples of both compounds were prepared by recrystallizationfrom benzene-hexane.

First isomer: Off-white solid, M.P. 7980.

Analysis.-Calcd. for C H N O S (percent): C, 56.22; H, 7.86; N, 10.93;S, 12.51. Found (percent): C, 56.40; H, 7.80; N, 10.81; S, 12.53.

Second isomer: Colorless solid, M.P. 98-99.

UV: A223? 223 m (6 6450), 243 (7150), 265 (14950); A2512 224 my. (611100), 247 (12000).

IR: v53; 3100-3400, 1595, 1555 emf; .335 3400, 3100-3400, 1710, 1605,1555 cmf NMR: 6%,? 3.33, 3.24, 2.68, 2.03, 0.92 .'m.'

MS: m/e 256 (M+ 241, 22s (M-28), 139, 43 (base) 19 Analysis.-Calcd. 'forC12H2'QN202S (percent): C, 56.22; H, 7.86; N, 10.93; S, 12.50. Found(percent): C, 56.41; H, 7.90; N, 10.82; S, 12.46.

Example 20 A mixture of 6 g. (32.2 mmoles) of 2-amino-7-oxa-3-thia-l-azaspiro[5.5]undec-1-ene prepared as in Example 12, 4.63 g. (33mmoles) of benzoyl chloride and 40 m1. of dry pyridine was stirred atroom temperature for six hours. The reaction mixture was poured intosaturated brine and extracted three times with ether. The combined etherextracts were Washed with brine, dried over anhydrous magnesium sulfate,filtered and concentrated at reduced pressure giving 9.3 g. of crudeproduct. This material was chromatographed on 100 g. of silica gel.Elution with 9:1 to 1:2 benzenezether mixtures aflforded 9.0 g. ofpale-yellow solid. Recrystallization from benzenehexane furnished 8.2 g.of racemic 2-benzamido-7-oxa-3- thia-l-azaspiro[5.5]undec-l-ene.

UV: 15:2? 245 m (e 12000), 285 (24500); 19.1f 255 (25200).

IR: 753;. 3100-3300, 1505, 1555 cmf 95,35 1550,

1595 cm. NMR: 39 3,? 8.19, 7.39, 3.73, 3.54, 2.72, 1.78 p.p.m. MS: m/e290 (M+), 262 (M-28), 105 (base).

. Ana'lysz's.Calcd. for C H N O S (percent): C, 62.05; H, 6.25; N, 9.65;S, 11.04. Found (percent): C, 61.88; H, 6.31; N, 9.43; S, 10.85.

Example 21 The following compounds were prepared in a similar manner asthat described in Example 20 from 2-amino-7-oxa-3-thia-l-azaspiro[5.5]undeo-1-ene and the appropriate acid chloride.

Racemic 2 p-fluorobenzamido-7-oxa-3-thia-l-azaspiro-[5.5]undec-1-ene.Colorless solid, M.P. 150.5151.5 from ethanol orbenzenehexane.

UV: 15 3 249 m1. (c 11200), 290 (25300); 39.12 m 213 (8840), 258(23600). IR: v53, 3100-3300, 1610, 1555 cmf NMR: 593% 12.75, 8.25, 7.07,3.83, 3.57, 2.83, 1.90

m/e 308 (M+), 280 (M-28), 123 (base).

Analysis.Calcd. for C H FN O S (percent): C, 58.42; H, 5.56; N, 9.08; S,10.40. Found (percent): C, 58.38; H, 5.80; N, 8.93; S, 10.50.

This material gave a hydrobromide salt as colorless solid M.P. 178-180"from ethanol.

Analysis.-Calcd. for C H FN O S-HBr (percent): C, 46.28; H, 4.66; N,7.19; S, 8.23. Found (percent): C, 46.26; H, 4.70; N, 7.11; S, 8.40.

Racemic Z-p-bromobenzamido-7-oxa-3-thia-l-azaspiro-[5.5]undec-1-ene.Colorless solid, M.P. 1285-129 from benzene-hexane orethanol.

UV: 85,12? 257 m (6 15100), 295 (30200); A131,? m (510600), 267 (27000).

In: 555;, 3100-3300, 1595, 1555 515: 95,59 1595, 1555 cmf NMR: 395312.75, 8.10, 7.54, 3.52, 2.79, 1.84 p.p.m. MS: m/e 368 (M'*) 340 (M-28),144 (base).

Analysis.Calcd. for C H BrN S (percent): C,

48.79; H, 4.64; N, 7.58; S, 8.68; 'Br, 21.68. Found .(percent): C,48.90; H, 4.75; N, 7.53; S, 8.99; Br, 21.33.

Racemic 2 pmethoxybenZamido-7-oxa-3-thia-l-azaspiro-[5.5]undetz-il-ene-Colorlesssolid, M.P. 104-107 from benzene-hexane. UV: 1523? 221 m (6 12250), 302(35000), m 15200), 257 (11500), 297 (22100). IR: vfiffi 3100-3300, 1605,1555 om. NMR: 59, 3,3 12,75, 20, 5.89, 3.82, 3.58, 2.77, 1.83

was." 227 p.p.m. s: m/e 320 2 1v1-28), 111 (base).

Analysis.Calcd. for C H N O 'S (percent): C, 59.98; H,.6.29; N, 8.74; S,10.00. Found (percent): C, 59.93; H, 6.33; N, 8.67; S, 9.74.

Racemic 2-o-fluorobenzamido 7-oxa-3-thia-1-azaspiro-[5.5]-undec-1-ene.Colorless solid, M.P. -965" from ethanol.

UV: 13.39? 242 m (5 10800), 283 (22200); 32.13" 252 In (5 22300).

IR: 75533;, 3100-3300, 1505, 1555 cm.-

Raman: (4880 A., powder) v,,,,,,, 1607, 1563, 1535 emf. NMR: 3913,?8.05, 7.20, 3.74, 3.52, 2.75, 1.78 p.p.m. MS: m/e 308 (M 280 (M-28), 123(base).

Analysis.-Calcd. for C H FN O S (percent): C, 58.42; H, 5.56; N, 9.08;S, 10.40. Found (percent): C, 58.11; H, 5.49; N, 9.21; S, 10.57.

Racemic 2-p-chlorobenzarnido-7-oxa-3-thia-l-azaspiro-[5.5]undec-1-ene.-Pale-yellow solid, M.P. 1285- from ethanol.

UV: 33:3? 253 mu (6 14220), 293 (28400); 33.1,}? m 215 m (e 9900), 254(25420 IR: 753;, 3100-3300, 1505, 1555 cm? NMR: 59, ,3 8.13, 7.32, 3.71,3.52, 2.72, 1.25 p.p.m. MS: m/e 324 M+ 295 M-28 144 (base).

MS: m/e 348 (M+), 320 (51-28), 213, 135, 111.

Analysis.Calcd. for C H N O S (percent): C, 65.48; H, 8.09; N, 8.04; S,9.20. Found (percent): C, 65.56; H, 8.14; N, 7.98; S, 9.17. 1

Racemic 2 cinnamamido-7-oxa-3-thia-l-azaspiro[5.5]undec-1-ene.Pale-yellow, viscous oil which was converted to thehydrochloride an off-white solid, M.P. l77.5- 179 from ethanol.

UV: 13,333 223 m 6 14700 311 (37000 IR: 755,: 2400-3250, 1710, 1530,1595, 1570 cmr NMR: 53, 3,2 7.95, 5.79, 7.50, 7.43, 3.80, 3.53, 2.85,1.45-2.66 p.p.m.

Analysis.Calcd. for C1'7H20N2O2S.HCl (percent): C, 57.86; H, 6.00; N,7.94; S, 9.08. Found (percent): C, 57.67; H, 5.79; N, 7.77; S, 9.06.

Example 22 A solution of 5 g. (0.0308 mole) of 1,1-carbonyl diimidazolein 15 ml. of dry tetrahydrofuran was stirred at room temperature while asolution of 3.1 g. (0.03 mole) of ethoxyacetic acid in 5 ml. of drytetrahydrofuran Was added. Gas was evolved and the resulting solutionwas stirred for one hour. A slurry of 5.6 g. (0.03 mole) of 2amino-7-oxa-3-thia-l-azaspiro[5.5] undec-lene in 60 ml. of drytetrahydrofuran was then added in five minutes and the resulting mixturewas stirred at room temperature for 18 hours.

After treatment with 60 ml. of water and 200 m1. of saturated brine, theorganic material was extracted three times With methylene chloride. Thecombined organic extracts were Washed once with brine, dried overanhydrous magnesium sulfate, filtered and concentrated at reducedpressure. This gave 8.1 g. of crude, pale-yellow oily product.

A 7 g. sample of this material was chromatographed on 200 g. of silicagel. Elution with 1:1 bfinzwetether to 4:1

etherzethyl acetate gave 5.4 g. of yellow oily racemic 2-ethoxyacetamido-7-oxa-3-thia-I-azaspiro .5] undecl-ene IR: v23,3100-3400, 1700, 1600, 1555 cmf A solution of this material in 30 ml. ofethyl acetate was added to 2.3 g. of maleic acid dissolved in 50 ml. ofethyl acetate and the resulting solution was concentrated at reducedpressure. The white solid residue was recrystallized from ethyl acetategiving 6 g. of fiuffy, white solid maleate, M.P. 9697.5.

UV: x212? 212 m (5 20550), 200 (15020). NMR: 09 0.34, 4.20, 3.59, 2.00,2.40, 1.83, 1.23

p.p.m.

Analysis.Calcd. for C H N O S-C H O (percent): C, 49.48; H, 6.23; N,7.21; S, 8.25. Found (percent): C, 49.68; H, 6.34; N, 7.21; S, 828.

Example 23 Racemic 2-phenylacetacetamido-7-oxa 3thia-l-azaspiro[5.5]undec-1-ene was prepared from 2-amino-7-oxa-3-thia-1-azaspiro[5.5]undec-1-ene and phenylacetic acid using theprocedure described in Example 22. The free base was a pale-yellow oil.

IR: 3100-3400, 1710, 1000, 1550 cm..

The maleate was a colorless solid, M.P. 101-102 from ethyl acetate.

UV: 05.13. 209 ni (6 28050), 267 (16500).

NMR: 09 3 5 7.30, 0.34, 3.80, 3.74, 3.40, 2.85, 1.54-2.58

- p.p.m.

Analysis.-Calcd. for C1 H2gN2O2SC4H4O (percent): C, 57.13; H, 5.75; N,6.66; S, 7.62. Found (percent): C, 57.36; H, 5.73; N, 6.65; S, 7.72.

Example 24 A solution of 1 g. (5.38 mmoles) of 2-amino-7-oxa-3-thia-1-azaspiro[5.5]undec-l-ene and 0.675 g. (5.65 mmoles) of phenylisocyanate in 20 ml. of methylene chloride was stirred at roomtemperature for 1.5 hours then concentrated to dryness at reducedpressure. This material was triturated with benzene to give 1.4 g. oflight brown solid. Two recrystallizations from methanol gave tancrystals of racemic 2-(3-phenyl)ureido-7-oXa-3-thia-l-azaspiro[5.51undec-1-ene, M.P. 177-178".

UV: x523? 277 m (6 20000); x315 247 m (6 17820). IR: .gg 3425,3100-3400, 1700, 1025, 1575, 1510,

1440, emf. MS: m/e 305 (M 213, 186, 158, 119 (base), 111.

Analysis. Calcd. for C H N O S (percent): C, 58.99; H, 6.27; N, 13.76;S, 10.50. Found (percent): C, 58.94; H, 6.26; N, 13.77; S, 10.37.

Example 25 A solution of 1 g. (5.38 mmoles) of 2-amino-7-oxa-3-thia-1-azaspiro[5.5]undec-1-ene and 0.81 g. (5.45 mmoles) of phthalicanhydride in 15 ml. of dry pyridine was stirred at room temperature for5 hours then poured into saturated brine. The mixture was extractedthree times with ether and the combined extracts were washed once withbrine, dried over anhydrous magnesium sulfate, filtered and concentratedat reduced pressure.

The residue (0.9 g.) was chromatographed on 50 g. of silica gel. Elutionwith 4:1 and 1:1 benzenezether afforded 0.55 g. of pure racemic2-phthalimido-7-oxa-3- thia-l-azaspiro[5.51undec-l-ene as a colorlesssolid. Two

1118K. NMR: 09% 7.81, 4.22, 3.07, 3.22, 1.74 p.p.m. MS: m/e 316 (M+),288 (M-28), 144 (base).

Analysis.Calcd. for C H N O S (percent): C, 60.74; H, 5.10; N, 8.85; S,1013. Found (percent): C, 60.51; H, 4.82; N, 8.56; S, 10.01.

This material could also be prepared in a similar manner by treatment of2-amino-7-oxa-3 thia l-azaspiro [5.5]undec-1-ene with phthaloylchloride.

Example 26 A slurry of 0.624 g. (0.013 mole) of 50% sodiumhydride-mineral dispersion in 12 ml. of dry dimethylformamide (DMF) wasstirred with ice-bath cooling while a solution of 2.7 g. (0.0118 mole)of 2-acetamido-7- oxa-3-thia-1-azaspiro[5.5]undec-l-ene in 30 ml. of dryDMF was added dropwise over a 10 min. period. Hydrogen was evolved andthe mixture was stirred for 10 min. at 0-5 then for 1 hour at roomtemperature.

The reaction mixture was once again cooled in an ice bath while 1.45 ml.(0.0125 mole) of benzyl chloride in 15 m1. of DMF was added over 5 min.The ice bath was removed and the slurry was stirred at room temperaturefor 4 hours before addition of 3 ml. of water. The resulting solutionwas concentrated to dryness at reduced pressure and the residue wastaken up in ether and washed three times with 3 N aqueous hydrochloricacid. The acidic washes were combined and extracted once with ether. Theether extracts were discarded.

The acidic extracts were made alkaline with 10% aqueous sodium hydroxidesolution then extracted three times with ether. The ether extracts werecombined, washed with brine, dried and filtered. Solvent removal gave2.96 g. of yellow oily product which contained 2- (N benzylacetamido) 7oxa 3 thia 1 azaspiro [5.51-undec-1-ene.

This material was stirred and refluxed with 25 ml. of 2 N aqueoushydrochloric acid for 2 hrs. After cooling, the mixture was madealkaline with 10% sodium hydroxide solution and extracted three timeswith methylene chloride. The combined methylene chloride extracts werewashed once with brine, dried over anhydrous magnesium sulfate, filteredand concentrated at reduced pressure. This gave 2.5 g. of crude,crystalline rac. 2-benzylamino-7-oxa-3-thia-1-azaspiro[5.5]-undec-l-ene. Recrystallization from ethanolfurnished 1.682 g. of colorless crystals, M.P. 94- 95 C.

The analytical specimen was a colorless solid, M.P. 94.5- 95.5 (fromethanol).

v; x332? 210 m (e 18000 IR: 7011918 3430, 1030 emf.

1113K. NMR: 09, 3,3 7.34, 4.50, 4.12, 3.50, 3.08, 1.71 p.p.m. MS: m/e276 (M+), 248 (M-28) Analysis.Calcd. for C H N OS (percent): C, 65.18;H, 7.29; N, 10.13; S, 11.60. Found (percent): C, 65.51; H, 7.31; N,10.12; S, 11.69.

Example 27 Racemic 2-methylamino-7-oxa-3-thio-l-azaspiro [5 .5undec-l-ene was prepared by the procedure used in Example 26 startingfrom 2-acetamido-7-oxa-3-thio-l-azaspiro [5.5]undec-1-ene and methyliodide. The product was a colorless solid, M.P. 107.5 109 from ethanol.

UV: x39 210 m (e 10000 IR: v 345O, 1030 emf.

23 Analysis.-Calcd. for C H N OS (percent): C, 53.97; H, 8.05; N, 13.98;S, 16.00. Found (percent): C, 54.14; H, 8.01; N, 14.04; S, 15.91.

Example 28 A solution of 3 g. (0.0149 mole) of2-(diethylan1inoethyl)-tetrahydropyran-2-ol, 2.28 g. (0.015 mole) ofphenylthiourea, 15 ml. of glacial acetic acid and 50 ml. of toluene wasstirred and heated at reflux for 18 hours using a Dean-.Stark trap toremove water. The solution was then concentrated to dryness at reducedpressure. The residue was treated with ether and washed three times withdilute aqueous hydrochloric acid. The acid extracts were combined andWashed once with ether. The ether extracts were discarded.

The aqueous acid solution was made alkaline with 10% aqueous sodiumhydroxide solution and extracted three times with methylene chloride.The combined organic extracts were dried over anhydrous sodium sulfate,filtered and concentrated at reduced pressure giving 2.1 g. of red gum.

This material was chromatographed on 100 g. of silica gel. The fractionseluted with 9:1 benzene:ether afforded 0.922 g. of yellowsemi-crystalline material rich in the desired product.

A sample of this material was recrystallized twice from benzene-hexanegiving rac. 2-phenylamino-7-oxa-3-thia-1- azaspiro[5.5]undec1-enealternatively named as the tautomer, rac.2-phenylimino-7-oxa-3-thia-1-azaspiro[5.5] undecane, M.P. 103-104.5.

UV: 35,12? 261 mu (6 12700); A5212 226 III/.0 (6 13000). IR: 5353 3400,1585 MIL-1; 535 1040, 1000 cmr NMR: 5253 7.18, 3.05, 3.05, 3.32, 2.74,1.72 p.p.m.

MS: m/e 202 04+ 234 (M28), 111

Analysis.-Calcd. for C H N OS (percent): C, 64.09; H, 6.91; N, 10.68; 8,12.22. Found (percent): C, 63.86; H, 6.84; N, 10.54; S, 12.37.

Example 29 The following compounds were prepared from 2-amino-7-oxa-3-thia-1-azaspiro[5.5]undec-1-ene and either the appropriate acidchloride according to the method of Example 20 or the appropriate acidaccording to the carbonyldiimidazole method of Example 22:

Racemic 2- 3-trifiuoromethylbenzamido -7-oXa-3-thial-azaspiro[.5]undec-1-ene (acid chloride method). Colorless solid, M.P. 101-102(crystallized from ethan01).

UV: 53.2, 241 m (0 11200 202 (23000); 5315 250 Inn (0 23500).

IR: 555;, 3100-3400, 1020, 1005, 1500 cmf NMR: 09.53 8.40, 7.54, 3.73,3.50, 2.75, 1.80, p.p.m- MS: m/e 358 (M+), 330 (M-28), 173, 144 (base),111

Analysis.-Calcd. for C16H17F3N202S (percent): C, 53.62; H, 4.78; N,7.82; S, 8.95. Found (percent): C, 53.93; H, 4.89; N, 7.78; S, 9.19.

Racemic Z-m-fiuorobenzamido-7-oxa-3-thia-l-azaspiro [5.5]-undec 1 ene(carbonyldiimidazole method).- Colorless solid, M.P. 8586 (crystallizedfrom ethanol).

UV: 312? 245 m (6 11400 285 (23800); 19,15 m 255 m (0 24400 IR: 555;,3100-3400, 1010, 1555 cm.".

NMR: 5.033 12.70, 7.03, 7.20, 3.75, 3.00, 2.70, 1.80

p.p.m. MS: m/e 308 (M 280 (M-28), 144, 123, 111 (base).

Analysis.Calcd. for C15H1'1FN2O2S (percent): C, 58.42; H, 5.56; N, 9.08;S, 10.40. Found (percent): C, 58.71; H, 5.70; N, 9.09; S, 10.28.

Racemic 2-o-chlorobenzarnido-7-oxa-3-thia-l-azaspiro [5.5]undec-1-ene(acid chloride method).Colorless solid, M.P. 115.5-1l7 (crystallizedfrom ethanol).

UV: A222? 272 my. (0 17220); MEL}? 220 my. (0 17220), 251 (14800).

IR: 5533;; 3100, 3200, 1050, 1020, 1530 cmf NMR: 52%? 0.82, 3.78, 3.45,2.80, 2.30, 2.25, 1.75

p.p.m. MS: m/e 332 (M+), 317, 304 (M-28), 147 (base), 111.

Analysisr-Calcd. for C H N O S (percent): C, 65.03; H, 7.28; N, 8.43; S,9.64. Found (percent): C, 65.12; H, 7.29; N, 853; S, 9.44.

Racemic 2 p-nitrobenzamido-7-oxa-3-thia-l-azaspiro [5.5]undec-1-ene(acid chloride method).Pale-yellow solid, M.P. 170.5-172" (crystallizedfrom acetonitrile).

UV: 53:3, 244 m (6 12800 301 (22000 131, 205 m 6 20050 NMR: 52 3,212.72, 8.31, 3.80, 3.04, 2.80, 1.85 p.p.m. MS: m/e 335 M+ 307 (M28),150, 144, 111.

Analysis.-Calcd. for C15H17N3O4S (percent): C, 53.72; H, 5.11; N, 12.53;S, 9.56. Found (percent): C, 53.50; H, 4.99; N 12.64; S, 9.62

Racemic 2- 3,4,5-trimethoxybenzamido -7-oxa-3-thia-1-azaspiro[5.5]undec-1-ene (acid chloride method). Colorless solid, M.P.142.5143.5 (crystallized from ethanol).

UV: 1 :12 208 mp. (c 25400 131; m 200 m 3 13400 IR: 5353. ,3100-3400,1555 cmf NMR: 52 ,8 12.00, 7.52, 3.02, 3.00, 3.73, 3.00, 2.75,

1.82 p.p.m. MS: m/e 380 (M 195 (base), 144, 111.

Analysis.-Calcd. for C H N O' S (percent): C, 56.83; H, 6.36; N, 7.36;S, 8.43. Found (percent): C, 56.85; H, 6.35; N, 7.30; S, 8.63.

Racemic 2-(3,4-dimethoxybenzamido)-7-oxa-3-thia-1- azaspiro[5.5]undec 1ene (carbonylidiimidazole method).- Colorless solid, M.P. 129.5-131(crystallized from ethanol).

UV: 312. 231 m 6 14550 280 18450 313 22700 18.1.0 235 10700 286 11200315 13150 IR: 553;; 3100-3300, 1005, 1550 cmf NMR: 02 3,? 12.75, 7.83,0.00, 3.02, 3.77, 3.50, 2.73, 1.80 p.p.m.

MS: m/e 350 11+ 322 04-28 (base), 144, 111.

Analysis.Cald. for C17H22N204S (percent): C. 58.27; H, 6.33; N, 7.99; S,9.15. Found (percent): C, 58.38; H, 6.39; N, 7.96; S, 9.28.

Racemic 2-p-cyanobenzamido-7-oxa-3-thia-l-azaspiro- [5.5]undec-1-ene(acid chloride method).Colorless solid, M.P. 170.5-172 (crystallizedfrom acetonitrile). UV: A513 248 m (0 17000), 202 (24300);

255 m '6 31000). IR: 5515;, 3100-3400, 2225, 1505, 1555 cmf NMR: 09,5313.07, 8.50, 7.00, 3.77, 3.58, 2.75, 1.82

max.

.m. 54%: m/e 315 (M 287 (M-28), 144, 111 (base).

Analysis.-Calcd. for C H N O S (percent): 61.01; H, 5.44; N, 13.34; S,10.18. Found (percent): C, 60.86; H, 5.41; N, 13.29; S, 1019.

Racemic 2 p n-butoxybenzamido-7-oxa-3-thia-l-azaspiro[5.5]undec-1-ene(carbonyldiimidazole method).-

D Colorless solid, M.P. 108-109 (crystallized from ethanol).

UV: 18.2.2? 220 m 8 11900), 302 35200 1995 228 (6 15200 250 10900), 299(22000 IR: 755,: 3100-3400, 1005, 1585, 1550 001- NMR: 12.80, 8.14,0.80, 8.97, 3.74, 3.54, 2.72,

1.77, 0.96 p.p.m. MS: m/e 362 (M+), 334 (M-28), 144 (base), 111.

Analysis.Calcd. for C H N O S (percent): C, 62.96; H, 7.23; N, 7.73; S,8.84. Found (percent): C, 63.06; H, 7.30; N, 7.72; S, 8.98.

Racernic 2-p-methylbenzamido-7-oxa-3-thia-l-azaspiro- [5.5]undec-l-ene(acid chloride method).-Colorless solid, M.P. 173.5-175 (crystallizedfrom ethanol).

UV: 13,125 257 m (6 12000), 292 (27250 19,55 220 m (6 9800), 207 (28150IR: 5515;, 8100-3400, 1595, 1555 cmf NMR: 09, 3,9 8.05, 7.27, 3.78,3.00, 2.74, 2.88, 1.80

p.p.m. MS: rn/e 304 (M 276 (M-28), 144, 119 (base), 111.

UV: 1:319? 225 my 3 0300), 288 (0900), 205 (10000 19 ,5 w 220 my 4 11020247 12750).

IR: 7533; 8100-3400, 1740, 1555 cmr NMRzB 9, 3 3.00, 3.48, 2.08,1.50-2.84 p.p.m.

MS: m/e 300 (M'*), 272 (M-28), 144, 111 (base) Analysis.-Calcd. for C HN O S (percent): C, 51.98; H, 6.71; N, 9.33; S, 10.67. Found (percent):C, 51.98; H, 6.96; N, 9.16; S, 10.83.

Racemic 2 (2,6 dichlorobenzamido)-1-oxa-3-thia-lazaspiro[5.5]undec-1-ene(acid chloride method). Colorless solid, M.P. 1825-184 (crystallizedfrom ethanol).

UV: A322? 273 mu (6 22100); K951571101 254 14300 IR: 1123-3100-3400,1590, 1550 cmr NMR: 09 5,? 12.20, 7.28, 3.80, 3.57, 2.80, 1.82 p.p.m MS:m/e 358 (M 330 M-28 298, 178, 144, 111 (base).

Analysis.-Calcd. for C H Cl N O S (percent): C, 50.19; H, 4.49; N, 7.80;S, 8.93. Found (percent): C, 50.31; H, 4.57; N, 7.78; S, 8.93.

Racemic 2-o-methylbenzamido-7-oxa-3-thia-l-azaspiro [5.51undec-1-ene(acid chloride method-Colorless solid, M.P. 82-83 (crysallized fromethanol).

UV: 19,2, 250 my 6 10000 281 20400); (c 20050 NMR: 09 3 2 12.25, 7.88,7.24, 3.77, 3.52, 2.75, 2.58,

1.79 p.p.m. MS: m/e 304 (M 276 (M-28), 144, 111 (base).

Analysis.-Calcd. for C H N O S (percent): C, 63.14; H, 6.62; N, 9.21; S,10.54. Found (percent): C, 63.01; H, 6.79; N, 9.24; S, 10.81.

Racernic 2- (2-furoamido -7-oxa-3-thial-azaspiro [5.5 undec-l-ene (acidchloride method).-Colorless solid, M.P. 101-103 (crystallized fromethanol).

UV: 1512 208 m 6 9900 303 38800 13.15 6 8800), 258 10000 291 25800 IR:059;, 8100-3400, 1010, 1555 0m.

NMR: 09 12.40, 7.55, 7.23, 0.52, 3.75, 3.58, 2.07, 1.78 p.p.m.

MS: rn/e 280 04+ 252 M-28 144, 111 0500), 95.

max.

256 III 4 2 Analysis.Calcd. for C H N O S (percent): C, 55.71; H, 5.75;N, 10.00; S, 11.44. Found (percent): C, 56.00; H, 5.75; N, 10.02; S,11.52.

Racemic 2-(2 thenoamido) 7 oxa-3-thia-1-azaspiro [5.5]undec-1-ene(carbonyldiimidazole method).-Colorless solid, M.P. 115-116(recrystallized from ethanol).

UV: 15,125 202 01,. (c 12700 271 11700 307 20200 19,15 59 274 In, (015000 298 15800 NMR: 59% 12.50, 7.82, 7.49, 7.05, 3.75, 3.57, 2.75 1.77,p.p.m.

MS: m/e 296 (M 268 (M-28), 144, 111 (base) Analysis.-Calcd. for C H N OS (percent): C, 52.70; H, 5.44; N, 9.46; S, 21.63. Found (percent): C,52.41; H, 5.38; N, 9.44; S, 21.32.

Racernic 2 trimethylacetamido-7-oXa-3-thia-l-azaspiro [5.5]undec-1-ene(acid chloride method).Colorless solid, M.P. 124.5-125.5 (crystallizedfrom ethanol) UV: A212? 235 m (8 7350 208 17200 x399 227 12950 24011200).

NMR: 09% 3.07, 3.40, 2.70, 1.73, 1.17 p.p.m.

Analysis.-Calcd. for C H N O S (percent): C, 57.75; H, 8.20; N, 10.36;S, 11.86. Found (percent): C, 57.50; H, 8.24; N, 10.31; S, 11.71.

Racemic 2 rn-nitrobenzarnido-7-oxa-3-thia-l-azaspiro [5.5]undec-l-ene(acid chloride method).Pale-yellow solid, M.P. 126-127".

Analysis.-Calcd. for C H N O.,S (percent): C, 53.72; H, 5.11; N, 12.53;S, 9.56. Found (percent): C, 53.87; H, 5.07; N, 12.70; S, 9.73.

Racemic2(4-dimethylarninobenzamido)-7-oxa-3-thial-azaspiro[5.51undec-1-ene(carbonyldiimidazole method).Yellow solid, M.P., 1645-1655".

Analysis.Calcd. for C H N O (percent): C, 61.23; H, 6.95; N, 12.60; S,9.62. Found (percent): C, 61.29; H, 6.89; N, 12.76, S, 9.87.

Racemic 2 (l-naphthamido)-7-oxa-3-thia-l-azaspiro [5 .5 ]undec-l-ene(carbonyldiimidazole method) .Colorless solid, M.P. 1395-1405".

Analysis.-Calcd. for C H N O' S (percent): C, 67.03; H, 5.92; N, 8.23;S, 9.42. Found (percent): C, 67.34; H, 5.92; N, 8.23; S, 9.29.

Racemic 2 (2,4 dichlorobenzamido)-7-oxa-3-thia-lazaspiro[5.5]undec-1-ene(acid chloride method).- Colorless solid, M.P. 88-89.5.

Analysis.-Calcd. for C H Cl N O S (percent): C, 50.15; H, 4.49; N, 7.80;S, 8.92. Found (percent): C, 50.12; H, 4.49; N, 7.83; S, 8.93.

Racemic 2 (4-phenylbenzamido)-7-oxa-3-thia-l-aza spiro[5.5]undec-l-ene(carbonyldiirnidazole method).- Colorless solid, M.P. 147-148.

Analysis.Calcd. for C H N O S (percent): C, 68.83; H, 6.05; N, 7.64; S,8.75. Found (percent): C, 69.03; H, 6.05; N, 7.67; S, 8.73.

Racemic 2 nicotinamido-7-oXa-3-thia-1-azaspir0[5.5] undec-l-ene(carbonyldiimidazole method).-Colorless solid, M.P. 102.5-103.5.

Analysis.-Calcd. for C H N O S (percent): C, 57.71; H, 5.88; N, 14.42;S, 11.00. Found (percent): C, 57.96; H, 5.89; N, 14.64; S, 11.05.

Example 30 To a cold (ice-bath) solution of 16.3 g. (0.14 mole) of crude1-hexen-3,6-diol, 530 ml. of 1,2-dichloroethane (dried over anhydrouspotassium carbonate), and ml. (56.2 g. 0.77 mole) of diethylarnine wasadded 154 g. of activated manganese dioxide in portions with efficientstirring. The mixture was stirred at 0-5 for one hour, then at roomtemperature for 18 hours.

The mixture was filtered with suction and the filter F cake was washedthoroughly by slurrying several times 27 in fresh dichloroethane andrefiltering. The filtrate and washes were combined and concentrated atreduced pressure giving 22.7 g. of a red oil.

This material was treated with 150 ml. of ethyl acetate and 300 ml. of1.2 N aqueous hydrochloric acid. After vigorous shaking, the aqueouslayer was separated and extracted with 3-150 ml. portions of ethylacetate.

The aqueous acidic solution was made alkaline (pH 12) with 100 ml. of Naqueous sodium hydroxide solution and extracted with 4-150 ml. portionsof benzene. The benzene extracts were combined and washed twice with 50ml. portions of brine then dried and concentrated at reduced pressuregiving 10.2 g. of the Mannich base 6-diethylamino-hexan-4-on-l-ol[alternative nomenclature 2- Z-diethylaminoethyl -tetrahydrofuran-2- 01]as a yellow oil.

IR: vgge moo-3400,1715 Ont- NMR: 3,? 5.17, 3.87, 2.62, 1.87, 1.07p.p.n1. MS: m/e 187 (M+), 172 (M-).

Example 31 A mixture of 0.8 g. (4.3 mmoles) of Mannich base prepared asin the preceding example, 0.33 g. (4.3 mmoles) of thiourea, 13.5 ml. oftoluene and 4.3 ml. of glacial acetic acid was stirred and heated atreflux for three hours. The resulting solution was concentrated atreduced pressure. The residue was chilled and treated with excess 10%aqueous sodium hydroxide solution and the alkaline mixture was extractedseveral times with methylene chloride. The extracts were combined,washed with brine, then dried, filtered and concentrated at reducedpressure giving 0.4 g. of pale-yellow crystalline residue.Recrystallization from acetonitrile gave the pure racemic2-amino-7-oxa-3-thia-l-azaspiro[5.4]dec.-l-ene as paleyellow solid, M.P.143-145 IR: time 3300, 3350, 1650, 1590 01117 NMR: aggg 4.46, 3.95,3.08, 1.86 p.p.m.

MS: m./e 172 (M+), 144 (M-28) (base), 130, 97.

Analysis.Calcd. for C7H12N2OS (percent): C, 48.81; H, 7.02; N, 16.26; S,18.61. Found (percent): C, 48.65; H, 6.93; N, 16.01; S, 18.34.

Example 32 A mixture of 25.2 g. (0.122 moles) of crude ethyl 7-chloro-S-oxoheptanoate, 15.5 g. (0.25 moles) of ethylene glycol, 0.25 g.of p-toluenesulfonic acid monohydrate and 200 ml. of benzene was stirredand heated at reflux for five hours. A Dean-Stark trap was used tocollect water. The resulting mixture was cooled and Washed with excesssaturated aqueous sodium bicarbonate solution. The benzene layer wasremoved and the aqueous layer was extracted twice with ether. Theorganic solutions were combined, dried (Na SO filtered and concentratedat reduced pressure giving 29.4 g. of crude, orange, oily ketal ester7-chloro-5-oxoheptanoate ethylene ketal which was used without furtherpurification.

IR: 1721;; 1740 emr- Example 33 A mixture of 5.7 g. (0.15 mole) oflithium aluminum hydride and 300 ml. of anhydrous ether was stirred withice-bath cooling while a solution of the crude ester prepared as inExample 32 in 50 ml. of ether Was added dropwise over minutes. The icebath was removed and the resulting gray-green mixture Was stirred atroom temperature for three hours then decomposed by cautious dropwiseaddition of 11.5 ml. of water and 9 ml. of 10% aqueous sodium hydroxidesolution, again with ice bath cooling. After stirring at roomtemperature for 1.25 hours, the slurry was filtered with suction and thefilter cake was washed thoroughly with fresh ether. The filtrate andwashes were combined and concentrated at reduced pressure giving 23.4 g.of crude yellow, oily 2-(2-chloroethyl)-2-(4-hydroxybutyl)-1,3-dioxolane which was not purified further.

IR: V23 3400 cmr Example 34 A mixture of 2 g. (9.6 mmoles) of the crudehydroxy ketal prepared as in Example 33, 5 ml. of 3 N aqueous sulfuricacid, 15 ml. of water and 15 ml. of acetone was stirred at roomtemperature for three hours then poured into saturated brine. Theorganic materials were extracted three times with ether. The etherextracts were combined, washed once with brine then dried (MgSO filteredand concentrated at reduced pressure giving 1.3 g. of yellow oily7-chloroheptan-5-on-1-01. This crude material was used without furtherpurification.

IR: 1122;, 3400, 1715 cm.-

Example 35 The crude chloroketone prepared as in Example 34 was mixedwith 1.2 ml. of triethylamine. A solid began to precipitate after a fewminutes. The mixture was kept at room temperature for 2.5 hours, thendiluted with ether. The solid was broken up, filtered with suction andwashed well with ether. The filtrate and washes were combined andconcentrated at reduced pressure giving 1.05 g. of yellow oilyheptyl-6-en-5-on-1-ol which was used immediately with no furtherpurification.

IR: 3400, 1680, 1620 MIL-1.

Example 36 A solution of the crude vinyl ketone (7.9 mmoles), preparedas in Example 35, 0.6 g. (7.9 mmoles) of thiourea and 7 ml. of glacialacetic acid was stirred at room temperature for 18.5 hours thenconcentrated at aspirator pressure at 55. The residue was treated withether and extracted twice with 10 ml. of 1 N aqueous hydrochloric acid.The acid extracts were combined and washed with ether then made alkalinewith 10% aqueous sodium hydroxide solution and saturated with salt.

The alkaline mixture was extracted three times with methylene chloride.The combined methylene chloride extracts were dried (MgSO filtered andconcentrated at reduced pressure giving 0.85 g. of yellow, crystallineracemic 2-amino-7-oxa-3-thia- 1-azaspiro [5.5]undec-1-ene, identicalwith a sample prepared previously. Recrystallization from ethanol gavepale-yellow crystals, M.P. 136- 139.

Example 37 IR: 115;}; 1740 cmr' NMR: 3,? 3.93, 3.67 p.p.m.

This material could also be prepared in comparable yield by the ethyleneglycol, p-toluenesulfonic acid method in benzene with azeotropic waterremoval.

Example 38 A solution of 7 ml. of sodium bis-Z-methoxyethoxy aluminumhydride (70% solution in toluene) in 10 ml. of toluene was stirred withice bath cooling while solution of 2.2 g. of the crude ketal esterprepared as in Example 37 in 10 m1. of toluene was added dropwise during15 minutes. The resulting solution was stirred at room temperature for1.75 hours then cautiously poured onto a mixture of ice and 10% aqueoussodium hydroxide solution. The resulting mixture was extracted threetimes with ether then the ether extracts were combined, dried (MgSOfiltered and concentrated at reduced pressure giving 1.2 g. of crude2-(2-chloroethyl)-2-(Ii-hydroxypropyl)-1,3-dioxolane as a brown oil.This material was used with no further purification.

IR: v23 3400 emf.

This reduction could also be carried out in comparable yield usinglithium aluminum hydride in ether in the usual manner.

Example 39 A mixture of the crude hydroxy ketal (6.17 mmoles) preparedas in Example 38, 0.47 g. (6.17 mmoles) of thiourea, 6.2 ml. of glacialacetic acid, 0.2 ml. of water and 20 ml. of toluene was stirred at roomtemperature for 1.5 hours then at reflux for 2.75 hours. The resultingmixture was concentrated at reduced pressure and the residue was treatedwith ether and washed twice with dilute aqueous hydrochloric acid. Theacid extracts were combined and washed again with ether.

The acid solution was made alkaline with potassium carbonate andextracted three times with methylene chloride. The methylene chlorideextracts were combined, dried (MgSO filtered and concentrated at reducedpressure giving 0.7 g. of yellow solid racemic 2-amino-7-oxa- 3-thia 1azaspiro[5.4]dec-1-ene. This material was dissolved in hot ethanol andtreated with 0.47 g. maleic acid. Crystallization gave colorless maleatesalt, MP. 143- 144.

Example 40 A mixture of 3.04 g. (0.08 mole) of lithium aluminum hydrideand 360 ml. of dry ether was stirred with ice bath cooling while asolution of 9.1 g. (0.0535 mole) of methyl 6-oxo-7-octenoate in 40 m1.of ether was added dropwise over 25 minutes. The resulting mixture wasstirred at 5 for 1 hour then for 2 hours at room temperature. Aftercautious decomposition by dropwise addition of 6 ml. of water and 4.8ml. of 10% aqueous sodium hydroxide solution, in the cold, the mixturewas stirred an additional 1 hour at room temperature. The solids werefiltered and washed well with ether. The filtrate and washes werecombined, dried (MgSO refiltered and concentrated at reduced pressuregiving 7.0 g. of yellow, oily 7-octen-1,6-diol which was used withoutfurther purification.

IR: 7112;; 3350, 920, 990 omf NMR: 58, 3,3 5.556.08, 5.12, 4.05, 8.57,2.83, 1.43

A solution of the diol prepared in Example 40 (7 g.), 25.2 ml. ofdiethylamine and 186 m1. of 1,2-dichloroethane was stirred with ice bathcooling while 48.7 g. of activated manganese dioxide was added. Theresulting mixture was stirred at room temperature for 19 hours thenfiltered and the solids were washed well with methylene chloride. Thefiltrate and washes were combined and concentrated at reduced pressure.

The residual oil was treated with 100 ml. of 1.2 N aqueous hydrochloricacid and extracted three times with ethyl acetate. The acid aqueoussolution was made alkaline with sodium hydroxide solution and extractedfour times with benzene. The benzene extracts were combined, washed withbrine, dried (MgSO filtered and concentrated at reduced pressure giving2.4 g. oily l-diethylamino-octan-3-on-8-ol.

IR: 52.158400, 1715 cmr NMR: 3,3 3.62, 2.53, 1.47, 1.02 p.p.m. MS: m/e215 M+ 100, 86.

30 Example 42 A mixture of the Mannich base prepared as in Example 41(2.4 g.), 0.88 g. (0.0116 mole) of thiourea, 50 ml. of toluene and 17ml. of glacial acetic acid was stirred and heated at reflux for 3 hours.A Dean-Stark trap was used to collect water. The mixture was stirred for16 hours at room temperature then concentrated at reduced pressure. Theviscous residue was treated with 10% aqueous sodium hydroxide andextracted four times with methylene chloride. The extracts werecombined, washed with brine, dried (MgSO filtered and concentrated atreduced pressure giving 2.25 g. of dark oily racemic 2-amino-7-oxa-3-thial-azaspiro [5.6] dodecl-ene.

IR: 1 2;; 3300, 3400, 1620, 1580 emf.

Example 43 A solution of 1.1 g. (5.5 mmoles) of the crude aminothiazineprepared as in Example 42 in 10 ml. of pyridine was treated dropwisewith 0.55 ml. of benzoyl chloride. The mixture was stirred for 3 hoursat room temperature then treated with excess saturated sodiumbicarbonate solution and extracted three times with ether. The etherextracts were combined, washed with brine, dried filtered andconcentrated at reduced pressure giving 1.6 g. of oily racemic2-benzamido-7-oxa-3-thia-l-azaspiro[5.6] dodec-l-ene.

This material was chromatographed on g. of silica gel. Elution with 19:1benzenezether atforded 0.45 g. of product.

523? 287 my 6 11720 285 (15750), 828. 258 51,. (e 17180 MS: m/e 304 (W),276 158, 125, (base).

Example 44 Racemic 2-p-fluorobenzamido-7-oxa-3-thia-l azaspiro [5.4]dec-l-ene hydrochloride was prepared from 7-oxa-3-thia-l-azaspiro[5.4]dec-1-ene and p-fiuorobenzoylchloride in pyridinefollowed by treatment of the oily product with hydrogen chloride.Off-white solid, M.P. 193-194 (crystallized from methanol).

UV: x332? 247 my (6 11050 290 (24400 IR: 7,9 5,9 2250-3250, 1685, 1575,1555 cmr NMR: 5 55 8.80, 7.80, 4.10, 3.35, 2.85 p.p.rn.

Analysis.--Calcd. for C H FN O S-HCl (percent): C, 50.83; H, 4.88; N,8.47; S, 9.69. Found (percent): C, 50.82; H, 4.96; N, 8.38; S, 9.74.

Example 45 The following compounds were prepared from racemic2-amino-7-oxa-3-thia-1-azaspiro[5.4]dec-l-ene using the procedures (ofeither Example 20, 22, 24 or 26) described for the spirothiazinepyranseries:

Racemic 2acetamido-7-oxa-3-thia-l-azaspiro[5.4] dec-lene.

Racemic 2-benzamido-7-oxa-3-thia-1-azaspiro[5.41dec-1- ene.

Racemic 2-p-bromobenzamido-7-oxa-3-thia-l-azaspiro- [5.4]dec-1-ene.

Racemic Z-p-methoxybenzamido-7-oxa-3-thia-l-azaspiro- [5.4]dec-1-ene.

Racemic 2-o-fluorobenzamido-7-oxa-3-thia-l-azaspiro- [5.4]dec-1-ene.

Racemic 2-p-chlorobenzamido-7-oxa-3-thia-l-azaspiro- [5.4ldec-l-ene.

Racemic 2-(l-adamantanylcarboxamido)-1-oxa-3-thia-1-azaspiro[5.4]dec-1-ene.

Racemic Z-cinnamamidoJ-oxa-a-thia-l-azaspiro[5.4]

dec-l-ene.

Racemic 2-ethoxyacetamido-7-oxa-3-thia-1-azaspiro[5.4]

dec-l-ene.

33 Example 47 UV: 32:2? 272 m 16900); 251 13600 331 235 6400). IR:7011911 3400, 3100-3400, 1695, 1600, 1530, 1505 max. emf. 111/13.3%,?7.17, 6.50, 3.30, 2.77, 1.70 p.p.m. MS: m/e 350 (14+), 322 (M-28), 165(base), 144, 111.

Analysis. Calcd. for C H N 0 S (percent): C, 58.27; H, 6.33; N, 7.99; S,9.15. Found (percent): C, 58.39; H, 6.44; N, 7.72; S, 9.22.

Racemic 2-(l-phenyl-1-cyclopentanecarboxamido) 7-oxa-3-thia-1-azaspiro[5.5]undec-1-ene (carbonyldiimidazolemethod).Colorless solid, M.P. 114-115 (recrystallized from ethanol).

UV: 3512 235 m (e 3460), 273 (13620); 32.1.? m 215 my 4 13300 223 13430244 13900 IR: .55; 3100-3400, 1535, 1550 MIL-1.

13141839955 7.34, 3.66, 2.70, 1.69 p.p.rn.

MS: m/e 353 14+ 330 14-23 213, 111 (base, 91, 55-

Analysis. Calcd. for C H N O S (percent): C, 67.01; H, 7.31; N, 7.81; S,8.94. Found (percent): 'C, 66.85; H, 7.23; N, 7.79; S, 8.94.

Racemic 2-(l-methyl-l-cyclohexane carboxamido)-7-oxa-3-thia-1-azaspir0[5.5]undec-l-ene (carbonyldiimidazolemethod).-Colorless solid, M.P. 103-104 (recrystallized from ethanol).

max.

UV: 15:3? 236 m (e 6320), 269 (17300); (e 13300 247 11450 IR: 75.5;3100-3400, 1590, 1560 crnf NMR: 39, 3,8 3.74, 3.47, 2.73, 1.13,0.90-2.40 p.p.m. MS: m/e 310 (M 282 (M-28), 144, 111 (base), 55, 41.

Analysis.-Calcd. for C H N O S (percent): C, 61.90; H, 8.44; N, 9.02; S,10.33. Found (percent): C, 62.22; H, 8.49; N, 9.03; S, 10.23.

Example 48 A solution of 2.6 g. (0.0125 mole) of2-(2-chloroethyl)-2-(4-hydroxybutyl)-1,3-dioxolane, 0.95 g. (0.0125mole) of thiourea, 0.4 ml. of water and 50 ml. of glacial acetic acidwas stirred and heated under reflux for five hours then concentrated atreduced pressure. The residue was treated with ether and washed twicewith two 20 ml. portions of 1.5 N aqueous sulfuric acid. The acid washeswere combined and back extracted once with ether. The ether solutionswere discarded.

The acid solution was made alkaline with aqueous sodium hydroxidesolution, saturated with sodium chloride and extracted three times withmethylene chloride. The combined methylene chloride extracts were driedover anhydrous magnesium sulfate, filtered and concentrated at reducedpressure giving 1.65 g. of yellow crystalline racemic2-amino-7-oxa-thia-l-azaspiro[5.5]undec-1- ene.

This material was dissolved in hot ethanol and treated with 1 g. ofmaleic acid. Crystallization gave 1.75 g. of colorless maleate salt M.P.1'61-163.

Example 49 A mixture of 10.1 g. of racemic 2-p-fluorobenzamido-7-oxa-3-thia-1-azaspiro[5.5]undec-1-ene, 7.6 g. of d'(+)-camphorsulfonic acid and 250 ml. of ethanol was heated until all thesolids had dissolved then concentrated to a volume of approximately 70ml. at reduced pressure. After standing at room temperature for twohours and at 0 for 16 hours the solid was filtered, washed with ethanoland dried giving 8.9 g. of colorless solid, M.P. 149.5-151. Tworecrystallizations from ethanol gave pure(+)-2-p-fluorobenzamido-7-oxa-3-thia l-azaspiro [5.5]undec-1-ened-(+)-camphorsulfonic acid salt, M.P. 149.5-151; [111 -22.61 (c..=0.9862in CHCl Analysis.-Calcd. for C H FN O S-C H O (percent): C, 55.54; H,6.15; N, 5.18; S, 11.86. Found (percent): C, 55.66; H, 6.30; N, 5.19; S,11.93.

Example 50 A 0.3 g. sample of the salt prepared in Example 49 was shakenwith saturated aqueous sodium bicarbonate solution and extracted withmethylene chloride. After washing with brine and drying, the methylenechloride extract was concentrated at reduced pressure giving 0.169 g. ofcolorless (+)-2-p-fiuorobenzamido-7-oxa-3-thia-1-azaspiro[5.5]undec-1-ene, M.P. 108.5-1095; [111 +36.71 (c.=0.9780 inCHClg). The spectral properties of this material were essentiallyidentical to those of the racemic form.

Analysis.Calcd for C H FN O2S (percent): C, 58.43; H, 5.56; N, 9.08; S,10.40. Found (percent): C, 58.58; H, 5.69; N, 9.14; S, 10.27

Example 51 A mixture of 8.0 g. of racemic 2-p-fluorobenzamido-7-oxo-3-thia-1-azaspiro[5.51undec-1-ene, 6.2 g. 1-()-camphorsulfonic acidand ml. of ethanol was heated until all the solids had dissolved thenconcentrated at reduced pressure. The residue was recrystallized fromapproximately 45 ml. of ethanol. This gave 9.5 g. of colorless solid,M.P. 148.5-. Another recrystallization from ethanol (30 ml.) gave 7.2 g.of (-)-2-pfluorobenzamido-7-oxa-3-thia 1-azaspiro[5.5]undec-1- ene1-()-camphorsulfonic acid salt, M.P. 148.5-150"; [M]D +1957" (c.=1.017in CHCl Analysis.-Calcd. fOl' C15H17FN202S'C10H1604S (percent): C,55.54; H, 6.15; N, 5.18; S, 11.86. Found (percent): C, 55.53; H, 6.23;S, 11.71.

Example 52 A 6.4 g. sample of the salt prepared in Example 51 was shakenwith excess aqueous saturated sodium bicarbonate solution and themixture was extracted three times with methylene chloride. The methylenechloride extracts were combined, washed with brine, dried, filtered andconcentrated at reduced pressure giving 3.45 g. of colorless(-)-2-p-fiuorobenzamido-7-oxa-3-thia-1- azaspiro[5.51undec-1-ene, M.P.109-110; [111 -36.76 (c.=1.020 in CHCl The spectral properties of thismaterial were essentially identical to those of the racemic form and the(+)-enantiomer.

Analysis.--Calcd. for C15H17EN2O2S (percent): C, 58.43; H, 5.56; N,9.08; S, 10.40. Found (percent): C, 58.23; H, 5.64; N, 9.10; S, 10.14

Example 53 A solution of 0.55 g. (0.0033 mole) of 7-chloroheptan-5-on-1-ol and 0.258 g. of thiourea in 25 ml. of acetonitrile was stirredand heated at reflux for 18 hours. The solu- 35 tion was cooled to andthe resulting precipitate was filtered giving 0.33 g. of colorlessracemic 2-amino-7-oxa- 3-thia-1-azaspiro[5.5]undec-l-ene hydrochloride,M.P. 206209.

Neutralization with aqueous sodium hydroxide gave the free base, M.P.135-139".

Example 54 A mixture of 42.5 g. (0.237 mole) of methyl 8-chloro-6-oxooctanoate, 26.5 ml. of ethylene glycol, 0.4 g. of p-toluenesulfonicacid monohydrate and 490 ml. of benzene was stirred and heated at refluxfor five hours using a Dean-Stark trap to remove water. After coolingthe reaction mixture was washed with saturated aqueous sodiumbicarbonate solution. The aqueous phase was back extracted three timeswith ether. The organic solutions were combined, washed with brine,dried over anhydrous magnesium sulfate then filtered and concentrated atreduced pressure giving 49.7 g. of red, oily methyl8-chloro-6-oxooctanoate ethylene ketal.

IR: 1745 cm."

Example 55 A slurry of 4.65 g. of lithium aluminum hydride in 200 ml. ofdry ether was stirred with ice-bath cooling while a solution of 25 g.(0.10 mole) of the ester from the preceding example in 50 ml. of dryether was added dropwise over 30 minutes. The mixture was stirred at 0-5for 30 minutes then at room temperature for 2.5 hours. After cautiousdecomposition by the dropwise addition of 9.4 ml. of water and 7.4 ml.of 10% aqueous sodium hydroxide with ice-bath cooling, the mixture wasstirred at room temperautre for 1.5 hours. The solids were filtered withsuction and washed well with ether. The filtrate and washes werecombined and concentrated at reduced pressure giving 17.7 g. of yellow,oily 2-(2-chloroethyl)-2-(5-hydroxypentyl)-1,3-dioxolane.

Example 56 A solution of 2 g. of the ketal from the preceding example in16 ml. of acetone, 16 ml. of water and 5.4 ml. of 3 N aqueous sulfuricacid was stirred at room temperature for three hours. After dilutionwith saturated brine, the mixture was extracted four times with ether.The ether extracts were combined and dried over anhydrous magnesiumsulfate then filtered and concentrated at reduced pressure giving 1.15g. of 8-chlorooctan-6-on-1-ol.

IR: 2,; 3400, 1715 cm.*-.

Example 5 7 A solution of the ketone from the preceding example and0.486 g. of thiourea in 50 ml. of acetonitrile was stirred and heated atreflux for 17.5 hours. The solution was concentrated at reduced pressureand the residue was triturated under acetone. The resulting solid wasfiltered to give 0.38 g. of pale-yellow racemic 2-amino-7-oxa-3-thia-l-azaspiro[5.6]dodec-1-ene hydrochloride. Recrystallization frommethanol-ether gave colorless solid, M.P. 159-160".

Analysis.Calcd. for C H N OSHCI (percent): C, 45.66; H, 7.24; N, 11.83;S, 13.54. Found (percent): C, 45.80; H, 7.37; N, 11.84; S, 13.50.

Example 5 8 A solution of 1.25 g. (5.84 mmoles) of the isomeric mixtureof 2-amino-8-ethyl-7-oxa-3-thia-1-azaspiro[5.5] undec-l-ene, prepared asin Example 18, 0.75 g. (6.7 mmoles) of 2-methyl-1,3-cyclopentandione,0.25 g. of ptoluenesulfonic acid monohydrate, 10 ml. of water and ml. ofdioxane was stirred and heated at reflux, under 36 nitrogen, for 99hours. After cooling, the mixture was poured into dilute aqueoussulfuric acid and extracted three times with ether. The ether extractswere combined, Washed With saturated aqueous sodium bicarbonatesolution, dried, filtered, and concentrated at reduced pressure, giving0.685 g. of red oil.

This material was stirred and heated at reflux, under nitrogen, for 0.5hour, in 10 ml. of benzene containing 25 mg. of p-toluenesulfonic acidmonohydrate. A Dean- Stark trap was used to collect water. The solutionwas cooled, diluted with ether and Washed once with aqueous sodiumbicarbonate solution then dried, filtered and concentrated at reducedpressure giving 0.558 g. of orange solid.

This material was chromatographed on 25 g. of silica gel. Elution with19:1 benzenezether afforded 0.454 g. of racemic 3ethyl-6a-methyl-1,2,3,5,6,6a-hexahydrocyclopenta[f][1]benzopyran 7(8H)one. Recrystallization from hexane-ether gave orange crystals, M.P.101-103.5.

UV: x1333? 254. mp (6=18200). IR: .355 1750, 1645 cmr The aqueoussulfuric acid solution from the above workup was made alkaline withpotassium carbonate, saturated with salt and extracted three times withmethylene chloride. The organic extracts were combined, dried, filteredand concentrated at reduced pressure. Solvent rernoval gave recoveredstarting aminothiazine mixture.

Example 59 A solution of 1.25 g. (6.26 mmoles) of the isomeric mixtureof Z-amino-8-methyl-7-oxa-3-thia-azaspiro[5.5] undec-l-ene prepared asin Example 10, 0.82 g. (7.3 mmoles) of 2-methyl-1,3-cyclopentandione,0.28 g. of ptoluenesulfonic acid monohydrate, 10 ml. of water and 20 ml.of dioxane was stirred and heated at reflux, under nitrogen for sevendays. Work-up as in the previous experiment gave 0.783 g. of orangesemi-solid.

This material was treated with p-toluenesulfonic acid (25 mg.) in 10 ml.of benzene as in the preceding experiment to give 641 mg. of orangesolid. Chromatography over 30 g. of silica gel afforded 459 mg. oforange, solid, racemic 3,6a dimethyl 1,2,3,5,6,6a hexahydrocyclopenta[f] [1]benzopyran-7(8H) -one.

Recrystallization from benzene-hexane gave orange, solid, M.P.. -148.

UV: x3323 254 mp. (e 17600). IR: .359 1740, 1640 cmr Example 60PARENTERAL FORMULATION 2 amino-7-oxa-3-thia-1-azaspiro[5.5]undec-l-enewas prepared in duplex ampuls, one containing the dry drug and the othercontaining water for injection, U.S.P.

Immediately before use the powder was solubilized with the followingsolution:

Water for injection, U.S.P.

Example 61 PARENTERAL FORMULATION Mg. per ml. Drug 10.0

Racemic 2-phthalimido-7-oxa-3-thia-l-azaspiro [5.5]undec-1-ene(micronized);

37 Racemic 2 p-fluorobenzamido-7-oxa-3-thia-1- azaspiro[5.5 undec-l-ene(micronized); or Racemic Z-cinnamamido 7oxa-3-thia-1-azaspiro[5.5]undec-1-ene hydrochloride Sodium chloride 9.0Sodium carboxymethyl cellulose, #7L2 2.5 Benzyl alcohol 9.0 Sodiumacetate 3H O 0.2 Acetic acid glacial 0.3 Water for injection qs add 1.0ml.

1) The sodium chloride benzyl alcohol, sodium acetate and acetic acidWere added in that order in part of the Water for Injection withconstant stirring.

(2) The sodium carboxymethyl cellulose was added with constant stirringuntil completely hydrated.

(3) The micronized drug was added with stirring to obtain a homogeneoussuspension. The suspension was then brought to volume with Water forInjection, filled into 2 cc. flint ampuls, sealed and sterilized at 212F. for 30 minutes.

Example 62 TABLET FORMULATION Amijel B011 1 20 Calcium stearate 8 Totalweight 410 1 A prehydrolyzed food grade corn starch. Any similarprehydrolyzed corn starch may be used. Purchased from: Corn ProductsCompany, 10 E. 56th St., New York, N.Y.

Procedure:

(1) The drug, lactose, corn starch and Amijel B011 were blended in asuitable mixer.

(2) The mixture was granulated to a heavy paste with water and the moistmass Was passed through a #12 screen. It was then dried overnight at 110F.

(3) The dried granules were passed through a #16 screen and transferredto a suitable mixer. The calcium stearate was added and mixed untiluniform.

(4) The mixture was compressed at a tablet weight of 410 mg. usingtablet punches having a diameter of approximately (Tablets may be eitherflat or biconvex and may be scored if desired.)

Example 63 CAPSULE FORMULATION Mg. per capsule Drug l 2 amino7-oxa-thia-l-azaspiro[5.5]undec-lene maleate Racemic 2 phthalimido7-oxa-3-thia-1-azaspiro [5.5]undec-1-ene Racemic 2p-fluorobenzamido-7-oxa-3-thia-lazaspiro[5.5]undec-1-ene or Racemic 2cinnamamido 7-oxa-3-thia-1-azaspiro [5.5] undecl-ene hydrochlorideLactose, U.S.P. 165 Corn starch, U.S.P. 30 Talc, U.S.P.

Total weight 210 Procedure:

(1) The drug, lactose and corn starch were mixed in a suitable mixer.

2) The mixture was further blended by passing through a FitzpatrickComminuting Machine with a #1A screen with knives forward.

(3) The blended powder was returned to the mixer, the talc added andblended thoroughly.

(4) The mixture was filled into #4 hard shell gelatin capsules on aParke Davis capsulating machine. (Any similar type capsulating machinemay be used.)

Example 64 TABLET FORMULATION Mg. per tablet Drug 25 2 amino7-oxa-3-thia-1-azaspiro[5.5]undec-1- ene maleate Racemic 2 phthalimido7-oxa-3-thia-1-azaspiro[5.5]undec-l-ene Racemic 2p-fiuorobenzamido-7-oxa-3-thia-1- azaspiro[5.5]undec-1-ene or Racemic 2cinnamamido 7-oxa-3-thia-1-azaspiro [5.5 ]undec-1-ene hydrochlorideDicalcium phosphate dihydrate, unmilled 175 Corn starch 24 Magnesiumstearate 1 Total weight 225 Procedure:

(1) The drug and corn starch were mixed together and passed through an#00 screen in Model J Fitzmill with hammers forward.

(2) This premix was then mixed With dicalcium phosphate and one-half ofthe magnesium stearate, passed through a #1A screen in Model J Fitzmillwith knives forward, and slugged.

(3) The slugs were passed through a #2A plate in a Model D Fitzmill atslow speed with knives forward, and the remaining magnesium stearate wasadded.

(4) The mixture was mixed and compressed.

Example 65 CAPSULE FORMULATION Mg. per capsule Drug 2 amino 7 oxa 3 thia1 azaspiro[5.5]

undec-l-ene maleate Racemic 2 phthalimido 7 oxa 3 thia 1- azaspiro [5.5]undecl-ene Racemic 2 p fluorobenzamido 7 oxa 3- thia-l-azaspiro[5 .5Jundec-l-ene or Racemic 2 cinnamamido 7 oxa 3 thia-lazaspiro[5.5]undec-1-ene hydrochloride Lactose, U.S.P. Corn starch, U.S.P. 30 Talc,U.S.P. 5

Total weight 210 Procedure:

(1) The drug was mixed with lactose and corn starch in a sutiable mixer.

(2) The mixture was further blended by passing through a FitzpatrickComrninuting Machine with a #1A screen with knives forward.

(3) The blended powder was returned to the mixer, the talc added andblended thoroughly.

(4) The mixture was filled into #4 hard shell gelatin capsules on aParke Davis capsulating machine.

Example 66 TABLET FORMULATION 'Mg. per tablet Drug 200 2 amino 7 oxa 3thia 1 azaspiro[5.5]

undec-l-ene maleate Racemic 2 phthalimido 7 oxa 3 thia 1- azaspiro [5 .5undecl-ene Racemic 2 p fluorobenzamido 7 oxa 3- thia-1-azaspiro[5 .5]undec-1-ene or Racemic 2 cinnamamido 7 oxa 3 thia-1- azaspiro[5.5]undec-1-ene hydrochloride Dicalcium phosphate dihydrate, unmilled235 Corn starch 70 FD & C Yellow .#5--Aluminum Lake 25% 2 Durkee 117 25Calcium stearate 3 Total weight 535 Procedure:

(1) All the ingredients were mixed thoroughly and Fitzed (Model D) usinga #1A screen, medium speed.

(2) The mixture was remixed and slugged.

(3) The slugs were screened on an oscillator through a #14 mesh screenand compressed on an E machine.

Example 67 SUPPOSITORY FORMULATION Gm. per 1.3 gm. suppository Drug0.025

2 amino 7 oxa 3 thia 1 azaspiro- [5.5]undec-1-ene maleate Racemic 2phthalimido 7 oxa 3 thia- 1-azaspiro[5.5]undec-1-ene Racemic 2 pfluorobenzamido 7 oxa 3- thia-l-azaspiro[5.5]undec-1-ene or Racemic 2cinnamamido 7 oxa 3 thial-azaspiro [5.5 ]undec-1-ene hydrochlorideWecobee M 1.230

Carnauba wax 0.045

E. F. Drew Company, 522 5th Ave, New York, N.Y.

Procedure:

(1) The Wecobee M and the carnauba wax were melted in a suitable sizeglass lined container (stainless steel may also be used), mixed well andcooled to 45 C.

(2) The drug which had been reduced to a fine powder with no lumps, wasadded and stirred until completely and uniformly dispersed.

(3) The mixture was poured into suppository molds to yield suppositorieshaving an individual weight of 1.3 gms.

(4) The suppositories were cooled and removed from molds. They wereindividually wrapped in wax paper for packaging. (Foil may also beused.)

Example 68 The mixture of isomers of racemic 2-amino-8-phenyl- 7 oxa 3thia 1 azaspiro[5.5]undec 1 ene prepared as in Example 7 was treatedwith p-bromobenzoyl chloride in the usual fashion. After chromatography,the 2 isomers of racemic 2-p-bromobenzamido-8-phenyl-7- oxa 3 thia1-azaspiro[5.5 ]undec-1-ene were isolated:

Isomer 1-Colorless solid, M.P. 126.5-127.5.

Analysis.Calcd. for C H BrN O S (percent): C, 56.63; H, 4.75; N, 6.29;S, 7.20. Found (percent): C, 56.62; H, 4.87; N, 6.12; S, 7.32 and Isomer2--Colorless solid, MP. 157-157.5.

Analysis.Calcd. for C H BrN O S (percent): C, 56.63; H, 4.75; N, 6.29;S, 7.20. Found (percent): C, 56.48; H, 4.70; N, 6.15; S, 7.25.

40 We claim: 1. A compound of the formula NH2 5 l.

m fln where R is hydrogen, lower alkyl, phenyl, 3,5-di(loweralkyl)-isoxazol 4 yl ethyl, 4,4 lower alkylenedioxyl-pentyl or4,4-phenylenedioxy 1 pentyl or 3-cyanopropyl; n is an integer of from 1to 3; and the tautomers, enantiomers and acid addition salts thereof.

2. The compound of claim 1 wherein R is hydrogen. 3. The compound ofclaim 2 which is 2-amino-7-oxa- 3-thia-1-azaspiro[5.4]dec-1-ene. 4. Thecompound of claim 2 which is 2-amino-7-oxa- 3-thia-1-azaspiro[5.5]undec-1-ene.

5. The compound of claim 2 which is 2-amino-7-oxa- 3-thia-1-azaspiro [5.6] dodecl-ene.

6. The compound of claim 1 wherein n is 2. 25 7. An process for thepreparation of a compound of the formula S nNH;

where 7 R is hydrogen, lower alkyl, phenyl, 3,5-di(lower alkyl)-isoxazol 4 yl ethyl, 4,4 lower alkylenedioxyl-pentyl or 4,4phenylenedioxy 1 pentyl or 3- cyanopropyl and n is an integer of from 1to 3,

which comprises reacting a compound of one of the formulas R and n areas above and X is halogen selected from the group consisting ofchlorine, bromine or iodine or a group of the formula where R, and R areeach independently lower alkyl or taken together are lower alkylene offrom four to six carbon atoms,

